Drugs in clinical development for multiple sclerosis: focusing on anti-CD20 antibodies

Introduction: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), traditionally considered to be an autoimmune disease. Despite the standard of care for patients with MS is significantly improved in recent years, there is still room for improvement in terms of effectiveness and also compliance.

Areas covered: The continuous improvements of our understanding of the pathophysiological changes that occur in MS have translated into many novel therapeutic agents at different stages of development. A number of therapies for MS are in advanced development and likely to be available soon. Along with these, we have also seen the appearance of a group of drugs considered together as a consequence of their similar design: the monoclonal antibodies (mAbs). Here, the focus will be on reviewing results that have emerged from a better clarification of MS pathogenesis to clinical trials of different anti-CD20 mAbs.

Expert opinion: The decision to switch established patients from well-known drugs to either new formulations or new agents will be made on balancing efficacy and tolerability of the existing treatments. Safety seems increasingly likely to become a key factor.     

Bladder symptoms in multiple sclerosis: a review of pathophysiology and management

Importance of the field: The use of anticholinergic medication in bladder dysfunction such as overactive bladder syndrome (OAB) is widespread. However, the benefits and risks of anticholinergics in multiple sclerosis (MS) are unclear because in MS the damage to normal urinary function is both more diffuse and increases with disease progression, and the risk of CNS side effects is higher.

Areas covered in this review: The pathophysiology of urinary dysfunction in MS and the efficacy and side effects of anticholinergics is assessed. The review analyzed randomized controlled trials and observational studies using anticholinergics involving persons with a confirmed diagnosis of MS having urinary symptoms. Finally a pragmatic approach to managing urinary symptoms in MS is discussed.

What the reader will gain: The published data provide limited evidence for the efficacy of anticholinergics in MS. The complexity of treating urinary symptoms in the context of other therapies and the changing neurological background seen in MS is comprehensively analyzed.

Take home message: Anticholinergics could be helpful in particular phases of MS. However, there is inadequate evidence currently available on the use of anticholinergics in MS, and further research on the management of the MS neuropathic bladder is warranted.     

Treatment of walking impairment in multiple sclerosis: an unmet need for a disease-specific disability

Introduction: Walking impairment is a clinical hallmark of multiple sclerosis (MS), a chronic neurologic disease characterized by axonal demyelination and dysfunction that results in progressive disability. Until recently, there were no therapies that specifically targeted the axonal dysfunction associated with walking impairment in MS.

Areas covered: The purpose of this review is to discuss the unmet need for the treatment of walking impairment in MS patients and to evaluate how a new class of pharmacologic therapies, neurofunctional modifiers, potentially addresses this unmet need. Discussion is based on clinical experience and opinions supported by publications identified in the PubMed literature using the search terms ‘multiple sclerosis’ and ‘mobility OR walking’.

Expert opinion: The development and approval of new treatments for MS show promise for improving adherence to therapy and increasing the potential for clinical effectiveness. Renewed emphasis on integrating strategies that target the underlying pathophysiology with those that address symptoms of concern to patients also has the potential to improve the lives of MS patients and their caregivers. The introduction of neurofunctional modifiers, such as dalfampridine for the improvement of walking impairment, may be of benefit by improving function, mobility and overall quality of life for MS patients.     

The role of myelin oligodendrocyte glycoprotein in autoimmune demyelination: a target for multiple sclerosis therapy?

Introduction: Myelin oligodendrocyte glycoprotein (MOG) is a myelin antigen at the outer surface of the central nervous system (CNS) myelin sheath, which may trigger T-cell as well as B-cell responses. It therefore constitutes a pivotal target for autoimmune responses, which result in inflammation and also demyelination in the CNS. In particular, it is a major target for auto-antibodies in experimental autoimmune encephalomyelitis (EAE), which mimics many aspects of multiple sclerosis (MS). B-cell responses toward MOG and anti-MOG antibodies have also been demonstrated in patients with demyelinating diseases, such as MS and acute disseminating encephalomyelitis (ADEM). Co-transfer of such anti-MOG antibodies in experimental models results in a distinct lesion pattern with antibody and complement-mediated demyelination, which is also hallmark of some lesion subtypes in MS.

Areas covered: A comprehensive literature search on MOG, B cells, MS, and ADEM was performed to outline the role of MOG in autoimmune demyelination in animal models and its relevance for human disease.

Expert opinion: Although the definite role of MOG in the pathogenesis of MS still remains to be clarified, innovative therapeutic strategies targeting B cells may reduce pathogenic immune responses against myelin auto-antigens including anti-myelin auto-antibodies.     

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.     

Can new chemical therapies improve the management of multiple sclerosis in children?

Introduction: Pediatric multiple sclerosis (MS) may represent up to 10% of all MS cases. Establishing the diagnosis of MS in a child is complicated by the limited diagnostic criteria and the possibility of significant overlap with acute disseminated encephalomyelitis.

Areas covered: This review puts in perspective the potential possibilities given by new pharmacological agents in pediatric MS; focusing on the unmet needs in terms of research development in this field.

Expert opinion: The treatment landscape of MS has dramatically changed in the last 5 years. However, children are receiving licensed therapies for adult MS (generally first line therapies) in an arbitrary manner and our understanding of such treatments effects and tolerability in children is limited. Of critical importance, we need clinical trials of newer MS agents in children. Further research is needed to have a positive impact for children with MS.     

Combination therapy for the treatment of multiple sclerosis: challenges and opportunities

ABSTRACT

Objective: Multiple sclerosis (MS) is a complex, heterogeneous disease. Standard treatment of relapsing MS includes interferon beta (IFNβ) and glatiramer acetate. These agents reduce relapse rates, and IFNβ?1a is associated with a slowing of disease progression. Despite treatment, many patients experience disease progression, prompting neurologists to use combination therapies to delay this progression. Agents that may be considered for combination therapy are those with unique mechanisms of action that exert additive or synergistic efficacy. This article reviews combination treatment with immunosuppressive therapies and new agents for the management of MS.

Methods: The Medline and EMBASE databases were searched for clinical trials using the following search terms: multiple sclerosis, interferon, Avonex, Betaseron, Rebif, glatiramer, copolymer 1, Copaxone, immuno­suppressant, cytotoxic, corticosteroid, azathioprine, cyclo­phosphamide, methotrexate, mitoxantrone, natalizumab, combination therapy. The National MS Society website was searched for clinical trials of combination therapies.

Results: Several small studies have analyzed the effects of immunosuppressive therapy added to IFNβ treatment, and some encouraging results have been obtained. Few data are available on combination therapy with new drug classes; however, current data suggest that combination therapy with new agents is effective. Although the available data on combination regimens are promising, interpretation is limited by lack of controlled study design, small patient population, and short study duration.

Conclusions: Combination of standard therapies with immunosuppressive agents or with new therapies may provide synergistic effects that will likely benefit patients with MS. Larger, well-controlled trials need to be conducted.     

Approaches to neuroprotective strategies in multiple sclerosis

Importance of the field: Multiple sclerosis (MS) is a neurologic disease that is the most common nontraumatic cause of serious disability in young adults.

Areas covered in this review: We discuss the natural history of the disease, methods of measuring disease activity and burden, and cellular and molecular mechanisms of damage, in particular recent advances. These imply new therapeutic targets, which are beginning to be tested in animal models of MS as well as in patients.

What the reader will gain: The reader will learn about some recent advances in understanding MS, especially the evolution from an inflammatory phase to a neurodegenerative phase, which have different therapeutic approaches.

Take home message: MS has a long-term course of accumulating deficit in which neuroinflammation evolves into neurodegeneration, which require different treatment strategies – immune modulation and neuroprotection. Neuroprotective strategies are still under development.     

Considerations on long-term immuno-intervention in the treatment of multiple sclerosis: an expert opinion

Introduction: As management of multiple sclerosis (MS) requires life-long treatment with disease-modifying agents, any risks associated with long-term use should be considered when evaluating therapeutic options.

Areas covered: Immune cells of the innate and adaptive immune systems play various roles in the pathogenesis of MS. MS therapies affect the immune system, each with a unique mode of action, and consequently possess different long-term safety profiles. Rare, but serious safety concerns, including an increased risk of infection and cancer, have been associated with immunosuppressant use. The risks associated with newer immunosuppressive agents, which target specific elements of MS disease pathophysiology, are not yet fully established as the duration of clinical trials is relatively short and post-marketing experience is limited. Non-immunosuppressants used to treat MS have well-defined safety profiles established over a large number of patient-years demonstrating them to be well-tolerated long-term treatment options. When considering the long-term use of disease-modifying agents for treating MS, classification as immunosuppressants or non-immunosuppressants can be useful when evaluating potential risks associated with chronic use.

Expert opinion: A successful therapeutic strategy for any serious, chronic disease such as MS should weigh effectiveness versus long-term safety of available treatments.     

Treatment of cognitive impairment in patients with multiple sclerosis

Introduction: Identifying and treating cognitive impairment in patients with multiple sclerosis (MS) is increasingly recognized as a crucial step in selecting the most appropriate treatment for the individual. Currently, the neuropsychological tests used to assess patients are time-consuming and require specialist training to administer; consequently, cognitive impairment in MS is underdiagnosed. Many treatments are available for MS, including disease-modifying drugs (DMDs) and symptomatic therapies, but what are their effects on cognitive performance?

Areas covered: This article will review published studies describing the cognitive effects of DMDs and symptomatic treatments for MS.

Expert opinion: Some DMDs may improve cognitive performance in patients with MS. None of the symptomatic drug treatments reviewed showed positive effects on cognitive performance, with the possible exception of L-amphetamine, which may improve memory in patients with existing deficits, and methylphenidate, on which more data are needed. Cognitive rehabilitation can improve cognitive performance, but experience with these techniques is limited. Treatment for patients with MS and cognitive impairment should, therefore, include a DMD in combination with a pharmacological or perhaps non-pharmacological cognitive-enhancement strategy. However, the methods used to diagnose cognitive impairment, and to assess the effect of treatment on function over time and need to be refined.     

RebiSmart™ (version 1.5) device for multiple sclerosis treatment delivery and adherence

Introduction: First-line disease-modifying drugs for the treatment of multiple sclerosis (MS) are mostly administered by injection. Although these treatments can control the symptoms and progression of the disease to some extent, patients often fail to adhere to their therapy in the long term, so may not obtain the maximum clinical benefits. As injection-related problems are common barriers to adherence, autoinjectors have been developed to improve the ease and convenience of self-injection.

Areas covered: This article discusses RebiSmart^?, an electronic autoinjector for the subcutaneous administration of interferon β-1a, focusing on the device features and data from clinical trials of the device. An overview of other available autoinjectors for first-line MS therapies is provided for context.

Expert opinion: The device is the first electronic autoinjector for use in MS and offers several innovative features, including adjustable injection settings and an electronic dosing log, which may improve adherence. The dosing log can be reviewed with the patient, allowing the physician to open a dialogue to discuss possible issues with treatment adherence. The use of multidose cartridges also provides a softer impact on the environment and easier disposal. The hidden needle helps avoid needle phobia and reduces the risk of needle stick injury.     

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.     

An evaluation of dimethyl fumarate for the treatment of relapsing remitting multiple sclerosis

ABSTRACT

Introduction

In recent years there has been a dramatic rise in available disease-modifying therapies for the treatment of relapsing multiple sclerosis (MS). Dimethyl fumarate (DMF) is an oral drug approved by the FDA for relapsing MS with unique immunomodulatory and cytoprotective effects.     

Recognizing and treating suboptimally controlled multiple sclerosis: steps toward regaining command

Abstract

Objective:

The therapies available today for multiple sclerosis (MS) reduce but do not fully control disease activity. The objective of this article is to review the definitions of and treatments for suboptimally controlled MS and highlight the challenges faced by clinicians to increase awareness of recognizing and managing patients with suboptimally controlled MS.     

A critical appraisal of daclizumab use as emerging therapy in multiple sclerosis

Introduction: Daclizumab (DAC) is a mAb that binds to CD25, a receptor on the surface of lymphocytes for IL-2, a chemical messenger in the immune system. This prevents activation and proliferation of lymphocytes, which are involved in the immune attack in multiple sclerosis (MS).

Areas covered: In this review, we will focus on newly emerging DAC-high-yield process (HYP) therapy for MS. Based on published original articles and citable meeting abstracts, we will discuss its mode of action as well as data on efficacy and safety.

Expert opinion: DAC has been observed to have multiple (biological) effects, which may contribute to beneficial effects in immune-related disease and particularly in relapsing-remitting MS. The positive results in the clinical studies represent achievement of an important milestone in the development of DAC-HYP as a potential new treatment option for MS patients. The benefit/risk ratios of this new biological agent in MS therapy are still being evaluated. Soon, DAC-HYP might qualify as MS therapy. A safety monitoring program is recommended in the clinical practice.     

Ibudilast for the treatment of multiple sclerosis

Introduction: Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS) characterized by inflammatory demyelination and progressive axonal loss. Clinically, this is manifest as relapsing and remitting neurological symptoms and progressive accumulation of disability. Ibudilast is a nonselective phosphodiesterase inhibitor which works by blocking the cleavage of cyclic adenosine monophosphate (cAMP). It has been found to have anti-inflammatory and neuroprotective properties in animal studies and in-vitro studies; it is currently being studied in progressive MS.

Areas covered: This article reviews various studies looking at ibudilast as a potential therapy for MS. It summarizes prior and current clinical trials of ibudilast in MS as well as its pharmacology.

Expert opinion: Although ibudilast has not been found to decrease the focal inflammatory activity in relapsing MS, it was shown to have an effect on preserving brain volume and disability progression. Ibudilast may have a role in the treatment of progressive MS phenotypes.     

Managing adverse effects of disease-modifying agents used for treatment of multiple sclerosis

ABSTRACT

Background: First-line agents approved in the United States for treatment of relapsing multiple sclerosis (MS) include intramuscular interferon beta (IFNβ)-1a, subcutaneous (SC) IFNβ-1a, SC IFNβ-1b, and SC glatiramer acetate. Intravenous mitoxantrone is the only agent approved for secondary progressive MS, progressive relapsing MS, and worsening relapsing MS. Intravenous natalizumab is approved for relapsing forms of MS generally in patients who have an inadequate response to, or are unable to tolerate, first-line therapies. Corticosteroids are commonly used to treat relapses. This paper reviews the incidence and management of common adverse events (AEs) associated with these treatments.

Methods: MEDLINE and EMBASE were searched for clinical trials and other publications between 1985 and 2007 reporting AEs associated with MS therapies, using these search terms: multiple sclerosis, interferon, Avonex, Betaseron, Rebif, glatiramer, copolymer 1, Copaxone, mitoxantrone, natalizumab, adverse events.

Results: A class-specific flu-like syndrome associated with IFNβ can be managed through initial dose escalation and administration of analgesics and antipyretics, prophylactically or symptomatically. Injection-site reactions can occur in patients receiving injectable therapies, particularly SC IFNβ or glatiramer acetate. The greatest risk to patients receiving mitoxantrone is cardiotoxicity; thus, the cumulative dose is limited. Allergic reactions occur rarely with natalizumab, and there is a potential risk of progressive multifocal leukoencephalopathy. AEs associated with short-term pulse corticosteroid therapy are usually transient and largely resolve after treatment is completed.

Conclusions: To improve adherence to therapy, it is important to educate patients regarding AEs and to manage AEs proactively.     

Results from the single-use autoinjector for self-administration of subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis (MOSAIC) study

Background: Patients with multiple sclerosis (MS) often receive long-term injectable therapy, and difficulties associated with self-injection can affect treatment adherence and efficacy.

Objective: The objective of this study was to evaluate an investigational, ready-to-use, single-use autoinjector for self-injection of subcutaneous (sc) interferon beta-1a (IFNβ-1a).

Methods: In this multicenter, open-label, single-arm study, patients with relapsing MS who were receiving IFNβ-1a sc 44 μg three times weekly for ≥ 12 weeks continued therapy using a single-use autoinjector and completed a user trial questionnaire at baseline and weeks 6 and 12. The primary endpoint was the proportion of patients rating the autoinjector as easy or very easy to use at week 12.

Results: At 12 weeks, 86% of 109 patients included in the intent-to-treat population rated the autoinjector easy or very easy to use (95% confidence interval, 80% ? 93%), and the most important perceived benefit was its overall convenience. The majority (74%) of patients reported the device as somewhat or extremely convenient to use, and most (83%) agreed or strongly agreed that the device made injections simple.

Conclusion: The single-use autoinjector was well received and supported by favorable ratings for simplified injections and convenience. The results suggest that the device may improve overall injection experience in patients with relapsing MS.     

Review of laquinimod and its therapeutic potential in multiple sclerosis

Introduction: Multiple sclerosis (MS) is a chronic immunological disease of the central nervous system characterized by early inflammatory demyelination and subsequent neurodegeneration. Although major progress has occurred, MS is still an incurable disease. Further, parenteral application and/or safety issues of the currently licensed drugs are associated with low patient compliance. Thus, there remains an unmet need for the development of more effective and well-tolerated oral therapies for the treatment of MS. At this point in time, different oral available substances are under investigation and hold promise in the treatment of relapsing-remitting MS (RRMS).

Areas covered: The physical, chemical and pharmacological properties of laquinimod, as well as its suggested mechanisms of action, clinical efficacy and side-effect profile are reviewed.

Expert opinion: Laquinimod is a new orally administered synthetic drug designed as an immunomodulator. Its mechanisms of action are not yet fully elucidated. Studies in mice and humans revealed different mechanisms of action, including anti-inflammatory and neuroprotective effects. So far, Phase II and Phase III clinical trials have shown its efficacy on magnetic resonance imaging based measures of disease activity, annualized relapse rate and disability progression in RRMS patients. Current data suggest a relatively modest efficacy by measures of relapse rate and there seems to be no superiority in comparison to established disease-modifying agents in relapsing-remitting MS. Further studies are necessary to evaluate both neuroprotective efficacy and optimal dosage of laquinimod in more detail.