Natalizumab for multiple sclerosis?

Around 2.5 million people worldwide have multiple sclerosis, of whom about 85,000 are in the UK.1Natalizumab (pronounced na-ta-liz-you-mab; Tysabri - Biogen Idec), the first in a new class known as selective adhesion-molecule inhibitors, is licensed in the UK as monotherapy for "highly active" relapsing/remitting multiple sclerosis.2 Here we review natalizumab and assess its place for patients with multiple sclerosis.     

Natalizumab in multiple sclerosis: proceed with caution?

Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the CNS. In a Phase II clinical trial, natalizumab was shown to reduce the relapses in patients with relapsing MS, without improving the disability score. After 1-year of Phase III clinical trials, natalizumab was approved by the FDA for use in relapsing MS but was withdrawn 3 months later, due to two reported cases of progressive multifocal leukoencephalopathy (PML). The completed clinical trials with natalizumab for relapsing MS have recently been reported. In a trial of 1171 subjects with relapsing MS, natalizumab alone was shown to reduce the relapse rate and lesions, without causing PML. Although natalizumab was also shown to reduce the relapse rates and lesions in patients taking IFN-β, two cases of PML with natalizumab occurred in these patients. An assessment of patients who had taken natalizumab for 1 – 2 years (～ 3000), showed the incidence of PML to be 1/1000. A drug that is useful in relapsing MS will be used as a long-term therapy in large numbers of patients. For instance, in the 3 months that natalizumab was registered, 5000 patients commenced taking it. In the author’s opinion, large numbers of patients should not be allowed to take natalizumab until its safety has been monitored in the long-term use in a clinical trial environment.     

Natalizumab in multiple sclerosis: proceed with caution?

Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the CNS. In a Phase II clinical trial, natalizumab was shown to reduce the relapses in patients with relapsing MS, without improving the disability score. After 1-year of Phase III clinical trials, natalizumab was approved by the FDA for use in relapsing MS but was withdrawn 3 months later, due to two reported cases of progressive multifocal leukoencephalopathy (PML). The completed clinical trials with natalizumab for relapsing MS have recently been reported. In a trial of 1171 subjects with relapsing MS, natalizumab alone was shown to reduce the relapse rate and lesions, without causing PML. Although natalizumab was also shown to reduce the relapse rates and lesions in patients taking IFN-beta, two cases of PML with natalizumab occurred in these patients. An assessment of patients who had taken natalizumab for 1 - 2 years (approximately 3000), showed the incidence of PML to be 1/1000. A drug that is useful in relapsing MS will be used as a long-term therapy in large numbers of patients. For instance, in the 3 months that natalizumab was registered, 5000 patients commenced taking it. In the author's opinion, large numbers of patients should not be allowed to take natalizumab until its safety has been monitored in the long-term use in a clinical trial environment.     

Treatment of multiple sclerosis during pregnancy – safety considerations

Introduction: Women with multiple sclerosis (MS) are treated early in the disease course with disease modifying therapies (DMT). Updated information is needed on pregnancy outcomes of DMT-exposed pregnancies and the effect of the drug withdrawal on MS disease activity.

Areas covered: In this review, we will cover the most important updated management strategies in planning a pregnancy when having MS.

Expert opinion: MS itself does not increase the risk of adverse pregnancy outcomes and does not negatively influence the long-term course of the disease. As MS became a treatable disease, management of DMTs before, during and after pregnancy is important. This requires updated knowledge on safety of DMTs as well as data of the effect on disease activity after drug withdrawal. A special challenge is the handling of women with highly active MS, as pregnancy might not be powerful enough to suppress the risk of rebound relapses. Exclusive breastfeeding is an option for many women who want to do so, but in cases of high disease activity and those women who do not want to breastfeed, early reintroduction of MS therapies should be considered.     

Early-stage multiple sclerosis : what are the treatment options?

Converging evidence from recent years indicates that the current attitude to the use of immunomodulatory drugs in the treatment of multiple sclerosis (MS) may be too conservative. This evidence originates from studies of the pathophysiology and pathology of MS, magnetic resonance imaging (MRI) studies and clinical trials. Several studies have shown that antigen spreading and propagation of self-recognition seem to occur during the clinical progression of MS. The immunopathology may change during the course of disease. Primary selective demyelination can be followed by a secondary oligodendrocyte loss and remyelination becomes less effective. MRI studies have shown that patients with clinically isolated syndromes, who at presentation have more than a few brain lesions on MRI, have a high risk of disease progression over a period of 5-10 years. The most direct evidence comes from two placebo-controlled trials of interferon-beta in very early MS. A delay in time to conversion to clinically definite MS and a significant decrease in MRI activity support an early stage treatment strategy. Taken together, the evidence indicates that treatment with immunomodulatory therapy should be started at an early stage in patients with a high-risk profile for further disease activity, although this may result in over-treatment of a small number of patients. However, further prolonged studies are needed to investigate the long-term benefit of early-stage treatment in MS.     

Triptolide inhibits T cell activation and proliferation via multiple pathways

Triptolide is potent immunosuppressive has been reported to inhibit autoimmunity, compound isolated from Chinese herbal medicine. Triptolide allograft attributed to the suppression of T cells via NF - kB rejection and GVHD, and its efficacy was previously pathway and apoptosis. In the present study, we detailedly analyzed Triptolide＇ s function on murine primary T cell. We found that Triptolide could inhibit T cell activation and proliferation by dramatically down - regulating cell division and cell cycle. Triptolide inhibited T cell activation in a dose- dependent manner, and the inhibition was mediated by both NF- kB pathway and AP - 1 pathway.     

What is new in the treatment of multiple sclerosis?

Multiple sclerosis (MS) is considered an autoimmune disease associated with immune activity directed against central nervous system antigens. Based on this concept, immunosuppression and immunomodualtion have been the mainstays of therapeutic strategies in MS. During the last decade new therapies have been shown to significantly improve MS disease course. The effective therapies have led to a better understanding of MS pathogenesis and further development of even more efficient therapeutic interventions. Recombinant interferon (IFN)beta represents the first breakthrough in MS therapy. Three large placebo-controlled, double-blind studies and several smaller studies have demonstrated the efficacy of different forms of IFNbeta administrated by either subcutaneous or intramuscular routes and at different doses in patients with active relapsing-remitting multiple sclerosis (RR-MS). The three IFNbeta drugs are IFNbeta-1b and two IFNbeta-1a preparations (Avonex and Rebif). Although each clinical trial had unique features and differences that make direct comparisons difficult, the aggregate results demonstrate a clear benefit of IFNbeta for decreasing relapses and probability of sustained clinical disability progression in patients with RR-MS. All forms of IFNbeta therapy had beneficial effects on the disease process measured by brain magnetic resonance imaging (MRI). IFNbeta-1a (Avonex) also showed benefit in slowing or preventing the development of MS related brain atrophy measured by MRI after 2 years of therapy. Glatiramer acetate, the acetate salt of a mixture synthetic polypeptides thought to mimic the myelin basic protein showed a significant positive results in reducing the relapse rate in patients with RR-MS. Follow up of these patients for approximately 3 years continued to show a beneficial effect on disease relapse rate. Recent MRI data supported the beneficial clinical results seen with glatiramer acetate in patients with RR-MS. Recent studies using intravenous immune globulin (IVIG) suggest that IVIG could be effective to some degree in patients with RR-MS. However, there is not enough evidence that IVIG is equivalent to IFNbeta or glatiramer acetate in the treatment of patients with RR-MS. There have also been recent therapeutical advances in secondary progressive MS (SP-MS). A recent large phase II, placebo-controlled study with IFNbeta-1b in patients with SP-MS convincingly documented that IFNbeta-1b slowed progression of the disease independent of the degree of the clinical disability at the time of treatment initiation and independent of presence of superimposed relapses. Mitoxantrone, an anthracenedione synthetic agent, was also shown to be effective as treatment for active SP-MS. It is well tolerated but the duration of treatment is limited by cumulative cardiotoxicity. There is a growing consensus that disease-modifying therapies should be initiated early in the course of the disease before irreversible clinical disability has developed. Different therapies should be considered and tailored based on patient condition. Combination therapies could be considered as a therapeutic option for patients that failed therapies with IFNbeta and/or glatiramer acetate. Currently, there are new ongoing studies testing safety and/or efficacy of different combination regimens (i.e. azathioprine with IFNbeta, IFNbeta with glatiramer acetate, or pulses of intravenous cyclophosphamide with IFNbeta). Determining the effect of different therapies on the course of the disease within large clinical studies appears easier than determining individual responsiveness. Therefore, standardised methods for evaluating individual patients receiving disease-modifying therapies and development of effective therapeutic algorithms are needed.     

Can yoga and climbing improve symptoms of multiple sclerosis?

Velikonja O, Čurić K, Ozura A, Jazbec SS. Influence of sports climbing and yoga on spasticity, cognitive function, mood and fatigue in patients with multiple sclerosis. Clin Neurol Neurosurg 2010; 112: 587–601.     

Interferon-beta in multiple sclerosis. Can we control its costs?

The recent licensing of interferon-beta for use in patients with multiple sclerosis has caused concern, in view of the equivocal evidence of efficacy, pressure of public expectation towards its use and the high expected cost if widespread use were to be sanctioned. Whether such alarm is justified remains a moot point. Owing to the limited range of circumstances of proven efficacy and the lack of cost-effectiveness data, it remains unclear whether sanctioned usage will proliferate to the anticipated extent. Unit costs may well fall in the future owing to competition in the pharmaceutical market. Interferon-beta is simply one example of a growing trend in actively promoted high-cost preparations over which rationing decisions will have to be reached.     

Animal models of anxiety: do I need multiple tests?

The combination of cutting-edge molecular technology and high-throughput phenotyping tools will not bring the expected contribution to the pre-clinical study of anxiety if not paralleled by an increase in our capacity to interpret behavioral data. Here, previous views about the multidimensional nature of emotional behaviors will be expanded and the psychological meaning and behavioral overlaps of widely used anxiety tests such as the open field, elevated plus maze and light-dark box will be discussed. It is proposed here that short-term, intra-individual variations in emotionality, although normally overlooked, constitute an important factor in the study of anxiety and can lead to unreliable estimates of the similarities between tests. The physical integration of different current tests in one single apparatus, in such a way that the emotional status of an animal becomes assessable through a series of distinct tasks, could contribute to increase reliability, rapidity and comprehensiveness in behavioral testing.     

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.     

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.