fumarates and laquinimod

New oral drugs have considerably enriched the therapeutic armamentarium for the treatment of multiple sclerosis. This review focuses on the molecular pharmacodynamics of fingolimod, dimethyl fumarate (BG-12), laquinimod, and teriflunomide. We specifically comment on the action of these drugs at three levels: 1) the regulation of the immune system; 2) the permeability of the blood-brain barrier; and 3) the central nervous system. Fingolimod phosphate (the active metabolite of fingolimod) has a unique mechanism of action and represents the first ligand of G-protein-coupled receptors (sphingosine-1-phosphate receptors) active in the treatment of multiple sclerosis. Dimethyl fumarate activates the nuclear factor (erythroid-derived 2)-related factor 2 pathway of cell defense as a result of an initial depletion of reduced glutathione. We discuss how this mechanism lies on the border between cell protection and toxicity. Laquinimod has multiple (but less defined) mechanisms of action, which make the drug slightly more effective on disability progression than on annualized relapse rate in clinical studies. Teriflunomide acts as a specific inhibitor of the de novo pyrimidine biosynthesis. We also discuss new unexpected mechanisms of these drugs, such as the induction of brain-derived neurotrophic factor by fingolimod and the possibility that laquinimod and teriflunomide regulate the kynurenine pathway of tryptophan metabolism.

Topics: Administration, Oral; Animals; Blood-Brain Barrier; Crotonates; Dimethyl Fumarate; Fingolimod Hydrochloride; Fumarates; Humans; Hydroxybutyrates; Immune System; Multiple Sclerosis; NF-E2-Related Factor 2; Nitriles; Propylene Glycols; Quinolones; Sphingosine; Toluidines

In Part 2 of this three part review of multiple sclerosis (MS) treatment with a particular focus on the Australian and New Zealand perspective, we review the newer therapies that have recently become available and emerging therapies that have now completed phase III clinical trial programs. We go on to compare the relative efficacies of these newer and emerging therapies alongside the existing therapies. The effectiveness of β-interferon in the treatment of different stages and the different disease courses of MS is critically reviewed with the conclusion that the absolute level of response in term of annualised relapse rates (where relapses occur) and MRI activity are similar, but are disappointing in terms of sustained disability progression for progressive forms of the disease. Finally we review the controversial area of combination therapy for MS. Whilst it remains the case that we have no cure or means of preventing MS, we do have a range of effective therapies that when used appropriately and early in the disease course can have a significant impact on short term and longer term outcomes.

Topics: Adult; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antigens, CD20; Antioxidants; Australia; Clinical Trials, Phase III as Topic; Crotonates; Daclizumab; Dimethyl Fumarate; Disease Management; Disease Progression; Drug Therapy, Combination; Evidence-Based Medicine; Fumarates; Hematopoietic Stem Cell Transplantation; Humans; Hydroxybutyrates; Immunoglobulin G; Immunosuppressive Agents; Interferon-beta; Magnetic Resonance Imaging; Multiple Sclerosis; New Zealand; Nitriles; Quinolones; Randomized Controlled Trials as Topic; Therapies, Investigational; Toluidines; Transplantation, Autologous; Treatment Outcome

The development of new disease-modifying drugs (DMD) in relapsing-remitting multiple sclerosis (RRMS), which share the common denominator of oral administration, considerably improves patient expectations in terms of effectiveness, tolerability and treatment adherence compared with currently available drugs. However, the common route of administration of these drugs does not mean that they are equivalent, since the heading of "oral route" encompasses drugs with distinct indications and mechanisms of action, as well as heterogeneous results in terms of efficacy and safety, allowing treatment to be personalized according to the each patient' s characteristics. Currently, four oral DMD are available or in an advanced stage of clinical development: fingolimod, teriflunomide, dimethyl fumarate and laquinimod. In pivotal trials versus placebo, these molecules reduced the annualized rate of exacerbations versus placebo by 54%, 31%, 53% and 23%, respectively, the risk of progression of disability by 31%, 30%, 38% and 36%, and the number of active lesions showing contrast uptake on magnetic resonance imaging by 82%, 80%, 90% and 37%, respectively. Based on the risk/benefit ratio, fingolimod is indicated in patients with suboptimal response to initial DMD or in severe rapidly progressing RRMS, while the remaining drugs can be used as first-line options. Clinical experience with these treatments will provide new data on safety and effectiveness, which will be determinant when establishing therapeutic algorithms.

Topics: Administration, Oral; Crotonates; Dimethyl Fumarate; Fingolimod Hydrochloride; Fumarates; Humans; Hydroxybutyrates; Immunosuppressive Agents; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Nitriles; Propylene Glycols; Quinolones; Sphingosine; Toluidines

Multiple sclerosis (MS) is an immune-mediated inflammatory disease of the central nervous system considered the second cause of disability in young adults. The prognosis of MS has improved significantly since the approval of the first interferon β in 1993 but, compared to other diseases, few new therapeutic products have been commercialized in the last years. However, currently, there are more than 600 ongoing clinical trials and new drugs that aim to improve efficacy and a more convenient schedule of administration, will appear shortly on the market. On the other hand, new safety issues will arise as well as a significant economic impact on the health system. The main efficacy and safety results of these drugs are reviewed in this paper. They can be classified into 2 groups: oral (fingolimod, laquinimod, teriflunomide, BG-12 [dimethyl fumarate], oral cladribine, dalfampridine) and monoclonal antibodies (rituximab, ocrelizumab, ofatumumab, daclizumab, alemtuzumab).

Topics: 4-Aminopyridine; Administration, Oral; Adult; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Cladribine; Clinical Trials as Topic; Crotonates; Daclizumab; Dimethyl Fumarate; Fingolimod Hydrochloride; Fumarates; Humans; Hydroxybutyrates; Immunoglobulin G; Immunosuppressive Agents; Middle Aged; Multicenter Studies as Topic; Multiple Sclerosis; Nitriles; Propylene Glycols; Quinolones; Rituximab; Sphingosine; Toluidines; Young Adult

2012 witnessed important developments for multiple sclerosis, including successful phase III trials of novel oral therapeutics and identification of the potassium channel KIR4.1 as an autoimmune target. Additionally, the lung was highlighted as an important site for immune-cell programming, and the relevance of a TNF receptor variant was clarified.

Topics: Clinical Trials as Topic; Dimethyl Fumarate; Fumarates; Humans; Immunosuppressive Agents; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Potassium Channels, Inwardly Rectifying; Quinolones; Receptors, Tumor Necrosis Factor, Type I; T-Lymphocytes

Several disease-modifying therapies are approved for the management of multiple sclerosis (MS). While reasonably effective, these therapies require long-term parenteral self-injection, which is inconvenient for some patients and can be associated with injection-related adverse effects. Consequently, there is a need in MS for an oral therapy option. Currently, five oral therapies are in phase III development or have recently been approved for the treatment of relapsing-remitting MS: cladribine (approved in Russia and Australia), fingolimod (approved in the US and Russia), BG-12 (phase III), laquinimod (phase III) and teriflunomide (phase III). While the availability of oral therapies has been much anticipated by physicians and patients, neurologists will need to be cautious in selecting such therapy, which may appear to have efficacy and convenience advantages versus current therapies, but may also carry novel safety and tolerability concerns. The decision to use these new therapies will most likely be based on an overall assessment of efficacy, safety, tolerability and adherence, the potential need for monitoring and cost effectiveness. The objective of this article is to review the currently available data for each of these new oral therapies, which addresses the mechanism of action, efficacy and safety, and to provide a perspective on the potential future role of these therapies within clinical practice. Although better patient compliance is expected with the oral agents compared with the injectables, the safety profiles of these new oral drugs will have to be watched carefully.

Topics: Administration, Oral; Cladribine; Clinical Trials, Phase III as Topic; Crotonates; Dimethyl Fumarate; Fingolimod Hydrochloride; Fumarates; Humans; Hydroxybutyrates; Multiple Sclerosis; Nitriles; Propylene Glycols; Quinolones; Sphingosine; Toluidines

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system and the most common cause of neurological disability in young adults, along with a considerable clinical and pathological heterogeneity. Since, current therapies appear to be modest in the magnitude of their treatment effects, particularly in the progressive phase of this disease, thus novel promising therapeutic strategies might open a light horizon in approaching to an efficient treatment in MS. In this review, we will discuss about relevant patents and novel designed immunosuppressive and anti-inflammatory oral drugs promising for treatment of multiple sclerosis.

Topics: Administration, Oral; Cladribine; Crotonates; Diterpenes; Epoxy Compounds; Fingolimod Hydrochloride; Fumarates; Humans; Hydroxybutyrates; Multiple Sclerosis; Nitriles; Patents as Topic; Phenanthrenes; Propylene Glycols; Quinolones; Sphingosine; Toluidines

Multiple sclerosis (MS) is an autoimmune and degenerative disorder. In the past decades, the introduction of parenteral immunomodulatory therapies brought significant progress. These agents increase the number of relapses (shubs) by about 30%, and some of them has been shown to halter the accumulation of neurological symptoms and the development of disability. As first-line agents, interferon beta and glatiramer acetate (consisting of amino acids) can be used. Some new therapeutic strategies have been developed as a result of biotechnological development. The advantage of humanised monoclonal antibodies is that they affect the autoimmune inflammatory process more selectively. Among monoclonal antibodies, natalizumab, which binds to alpha-4-beta-1 integrin receptors and inhibits the migration of T-lymphocytes into the central nervous system, is available from February 2010 in Hungary, recommended as second-line treatment. The efficacy of natalizumab in decreasing relapse rate is > 60%. However, its use is associated with progressive multifocal leukoencephalopathy (PML) in one out of 1000 treated patient. Currently it is recommended as second-line treatment, if the patient has active disease despite immunomodulatory therapy. Among orally administered agents, a preparation containing fingolimod is expected to become available next year, and another pill, cladribin has been also found to be efficient in randomised, controlled phase III trials. Fingolimod acts on sphingosine 1-phosphate receptors-1 (S1P1). Cladribine is a purine nucleotide analogue, and its efficacy is based on long-term reduction of CD4+ and CD8+ lymphocytes. Further promising oral immunomodulatory agents are laquinimod and BG000012 (dimethylfumarate), which are currently being tested in phase III clinical trials in relapsing-remitting MS. The most efficient treatment should be chosen on the basis of the activity, aetiology and the posited pathomechanism of the disease. With the increasing number of therapeutic options, choosing the treatment that is optimal for the patient while also considering side effects might be challenging for both the patients and physicians.

Topics: Administration, Oral; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Cladribine; Dimethyl Fumarate; Drug Administration Schedule; Fingolimod Hydrochloride; Fumarates; Glatiramer Acetate; Humans; Immunosuppressive Agents; Interferon-beta; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Natalizumab; Peptides; Propylene Glycols; Quinolones; Sphingosine; Treatment Outcome

The armamentarium for the treatment of relapsing-remitting multiple sclerosis (RRMS) is increasing rapidly. Several oral treatments have shown benefit and will generate much interest because of the convenience of such administration. However, availability of convenient oral drugs will not necessarily translate into clinical effectiveness and safety. Here, we provide an interim report about the mechanisms of action, and efficacy and safety results that have been reported since January, 2010, for five new oral drugs. Additionally, we draw attention to issues that neurologists and patients will encounter when considering the use of new oral drugs.. Positive results have been reported for five new oral drugs for RRMS--fingolimod, cladribine, teriflunomide, laquinimod, and dimethyl fumarate--in phase 3 studies; a few new oral drugs are likely to be approved for RRMS soon. WHERE NEXT?: Emerging oral treatments are ushering in a new era in the treatment of MS, providing not only new treatment options but also new challenges. Since data for some of the new drugs have not been reported in peer-reviewed journals yet and safety profiles are not yet fully developed, opinions about the use of these new oral drugs in practice are preliminary and tentative. Practice will evolve with time as information and experience accumulates. Of importance will be results from comparator trials, information about management of patients with breakthrough disease, results from long-term safety studies, and results of studies to assess the potential for neuroprotective effects of the new drugs.

Topics: Administration, Oral; Cladribine; Clinical Trials as Topic; Crotonates; Dimethyl Fumarate; Fingolimod Hydrochloride; Fumarates; Humans; Hydroxybutyrates; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting; Nitriles; Propylene Glycols; Quinolones; Sphingosine; Toluidines

The current treatments for multiple sclerosis (MS) are, by many measures, not satisfactory. The original interferon-β therapies were not necessarily based on an extensive knowledge of the pathophysiological mechanisms of the disease. As more and more insight has been acquired about the autoimmune mechanisms of MS and, in particular, the molecular targets involved, several treatment approaches have emerged. In this chapter, we highlight both promising preclinical approaches and therapies in late stage clinical trials that have been developed as a result of the improved understanding of the molecular pathophysiology of MS. These clinical stage therapies include oral agents, monoclonal antibodies, and antigen-specific therapies. Particular emphasis is given to the molecular targets when known and any safety concerns that have arisen because, despite the need for improved efficacy, MS remains a disease in which the safety of any agent remains of paramount importance.

Topics: Alemtuzumab; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antibodies, Neoplasm; Cladribine; Crotonates; Daclizumab; Dimethyl Fumarate; Encephalomyelitis, Autoimmune, Experimental; Fingolimod Hydrochloride; Fumarates; Humans; Hydroxybutyrates; Immunoglobulin G; Immunosuppressive Agents; Immunotherapy; Mice; Multiple Sclerosis; Myelin Basic Protein; Nitriles; Peptide Fragments; Propylene Glycols; Quinolones; Rituximab; Sphingosine; Toluidines; Vaccines, DNA

Disease-modifying treatments are now available in relapsing-remitting and secondary progressive multiple sclerosis (MS), and their beneficial effects have been shown in several clinical studies. However, as these treatments are only partially effective in halting the MS disease process and are frequently associated with side effects and suboptimal patient adherence, new oral therapeutic approaches are warranted. This review focuses on advances in current and novel oral treatment approaches for MS. Several pivotal reports have provided promising results for new oral therapies evaluating the safety and efficacy of new agents including fingolimod, fumaric acid, cladribine, teriflunomide and laquinimod.

Topics: Cladribine; Clinical Trials, Phase III as Topic; Crotonates; Fingolimod Hydrochloride; Fumarates; Humans; Hydroxybutyrates; Immunosuppressive Agents; Multiple Sclerosis; Nitriles; Propylene Glycols; Quinolones; Sphingosine; Toluidines

Therapy for multiple sclerosis (MS) has changed dramatically over the past decade, yielding significant progress in the treatment of relapsing/remitting and secondary progressive MS. Disease-modifying treatments are now widely available, and their beneficial effects on relapse rates, MRI outcomes and, in some cases, relapse-related disability have been shown in several clinical studies. However, as these treatments are only partially effective in halting the MS disease process and in clinical practice are frequently associated with injection-related side effects and suboptimal patient adherence, new oral therapeutic approaches are warranted.. The aim of the present paper is to present new promising results from emerging oral drugs for multiple sclerosis.. This review focuses on advances in current and novel oral treatment approaches for MS. Nevertheless, most of the data were obtained from Phase I/II clinical trials, we need further confirmation of their safety and efficacy profile from longer Phase III clinical trials.. Several pivotal reports have provided promising results for new oral therapies evaluating the safety and efficacy of new agents including fingolimod, fumaric acid, cladribine, teriflunomide and laquinomid.. It is unknown whether these oral drugs could be used as first-line treatment for MS; this will depend mostly on their safety profile. Alternatively, these drugs could be used as add-on treatment for failed first-line therapy, or as an effective induction agent.

Topics: Administration, Oral; Cladribine; Crotonates; Fingolimod Hydrochloride; Fumarates; Humans; Hydroxybutyrates; Immunosuppressive Agents; Multiple Sclerosis; Nitriles; Propylene Glycols; Quinolones; Sphingosine; Toluidines

In 1993, interferon beta-1b, the first clinically proven disease-modifying agent for multiple sclerosis, was approved, with several comparable agents following close behind. These agents have been beneficial in reducing relapse events and MRI lesions, but all require parenteral administration, leading some otherwise eligible patients to decline such therapies. Oral agents have been studied for decades with mixed results, but a small number of medications currently being tested in phase II/III clinical trials have shown promise in efficacy and tolerability. This review assesses the results of the more thoroughly studied of these agents, some of which may soon be approved for use in multiple sclerosis.

Topics: Administration, Oral; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Cladribine; Clinical Trials as Topic; Dimethyl Fumarate; Fingolimod Hydrochloride; Fumarates; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunosuppressive Agents; Interferon beta-1b; Interferon-beta; Isoxazoles; Leflunomide; Minocycline; Multiple Sclerosis; Mycophenolic Acid; Propylene Glycols; Pyridones; Quinolones; Sphingosine

Topics: Administration, Oral; Crotonates; Dimethyl Fumarate; Fumarates; Humans; Hydroxybutyrates; Immunologic Factors; Immunomodulation; Immunosuppressive Agents; Multiple Sclerosis; Nitriles; Quinolones; Toluidines

Topics: Alemtuzumab; Animals; Antibodies, Monoclonal, Humanized; Cladribine; Clinical Trials, Phase III as Topic; Crotonates; Dimethyl Fumarate; Disease Progression; Drug-Related Side Effects and Adverse Reactions; Fingolimod Hydrochloride; Fumarates; Humans; Hydroxybutyrates; Inflammation; Multiple Sclerosis; Natalizumab; Nitriles; Propylene Glycols; Quinolones; Risk Assessment; Sphingosine; Toluidines; United States; United States Food and Drug Administration

Multiple sclerosis (MS) represents the prototypic inflammatory autoimmune disorder of the central nervous system and the most common cause of neurological disability in young adults, exhibiting considerable clinical, radiological and pathological heterogeneity. A better understanding of the immunopathological processes underlying this disease have recently led to the design of numerous novel therapeutical approaches. Perhaps most importantly, therapy has changed dramatically over the past decade in that all relapsing forms of MS, including early forms of MS are now being treated relatively aggressively. However, there are still unmet needs in the management of this disease, especially since all of the currently available disease-modifying drugs are only partially effective. Most of the clinically relevant therapeutic agents are not yet available as oral formulations. A substantial number of pivotal and preliminary reports provide encouraging new evidence on advances being made in the development of oral therapies for MS. A different strategy is the development of very potent monoclonal antibodies, given intravenously or subcutaneously, many of which are being examined for clinical efficacy. These agents are potentially more effective, but may carry more serious side effects. Finally, drugs with a known good safety profile are being developed further. These advances are critically reviewed and put into perspective.

Topics: Administration, Oral; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Cladribine; Crotonates; Fingolimod Hydrochloride; Fumarates; Humans; Hydroxybutyrates; Immunologic Factors; Injections, Intravenous; Injections, Subcutaneous; Interferon-beta; Multiple Sclerosis; Nitriles; Propylene Glycols; Quinolones; Sphingosine; Toluidines