Pharmacological treatment of early multiple sclerosis

Currently, six medications are approved by the US FDA for the treatment of relapsing forms of multiple sclerosis (MS). In contrast, no pharmacological agent has proved to be effective in patients with secondary-progressive MS without relapses, or in patients with primary-progressive MS. One of the principal issues concerning an optimal pharmacotherapy for relapsing forms of MS is the optimal time of treatment initiation. There is now an almost universal consensus among MS experts that many patients will benefit from early therapy. However, several formidable challenges exist in identifying individuals who will benefit versus those who will do well without intervention. How do we define early MS and what clinical and paraclinical markers may be useful in defining the timing and nature of therapy? Do patients with a benign form of MS require therapy or are they exposed unnecessarily to adverse effects of our currently available medications? How do we identify disease progression and treatment failures? This review discusses these issues and outlines the evidence for application of 'early' treatment in patients with relapsing forms of MS.     

The safety and efficacy of IFN-beta products for the treatment of multiple sclerosis

Multiple sclerosis, a chronic demyelinating disease of the CNS, is now a treatable disease. Phase III clinical trials of three recombinant IFN-beta products conducted in relapsing-remitting multiple sclerosis have shown, albeit modest, significant effects on relapses and short-term progression of disability, and a more substantial effect on MRI parameters. However, these effects do not correlate well with clinical disease activity or long-term disability. Overall, IFN-beta is safe and generally well tolerated, and reported adverse events were comparable between preparations. Systemic side effects can be effectively managed by dose escalation, use of an auto-injector and careful clinical monitoring.     

Pharmacogenomics of the response to IFN-beta in multiple sclerosis: ramifications from the first genome-wide screen

Evaluation of: Byun E, Caillier SJ, Montalban X et al.: Genome-wide pharmacogenomic analysis of the response to interferon-beta therapy in multiple sclerosis. Arch. Neurol. 65(3) 337-344 (2008). Specifically, IFN-beta is the most widely used disease-modifying therapy for the treatment of multiple sclerosis. The main benefits of the therapy, fewer and less severe relapses as well as delayed disease progression, are seen in only approximately 50% of the patients. Genetic polymorphisms may constitute in-built determinants of individual differences in response to IFN-beta. Prior attempts to identify such 'predictors of response' were hypothesis-driven in that they were based on preselection of candidate genes associated with Type I interferon pathways. In the present study, the authors performed the first ever nonbiased genome-wide association screen in an attempt to identify response-predictive SNPs. Using a robust four-stage completion strategy coupled to advanced SNP ranking/clustering algorithms, 18 significant SNPs were identified, many of which are located in genes that have never before been linked clearly to Type I interferon biology or therapeutic effects. While this study was not designed per se so as to validate earlier findings, genes arising from previous pharmacogenomic studies were generally not confirmed. This is due to major discrepancies between interstudy sets of used SNPs, but may also reflect differential strategies for ascertainment of response to IFN-beta, or simply Type I/II errors. The 100-K SNP screen by Byun et al. hallmarks a new stage of pharmacogenomics research applied to multiple sclerosis treatments. Through the judicious implementation of DNA pooling on SNP microarrays, it vividly demonstrates that informative genome-wide pharmacogenomic screens can be performed at a fraction of the cost of individual microarray genotyping. Although, unquestionably, higher-density SNP screens and further replication studies are needed, this study is instrumental in bringing the concept of personalized medicine a (small) step closer to the multiple sclerosis patient. In addition, it has generated a flurry of novel information of likely importance in furthering our understanding of Type I interferon biology.     

Pharmacological management of depression in patients with multiple sclerosis

ABSTRACT

Introduction: The pharmacotherapeutic management of depression in patients with multiple sclerosis (MS) is a matter of debate that cannot be decided from the evidence available in the current literature. Therefore, its management essentially relies on the clinical experience of the prescribing clinician rather than on evidence-based approaches.

Areas covered: This review provides a clinically oriented critical perspective on the connection between MS and major depressive disorder (MDD) or depression associated with bipolar disorder (BD), focusing on its optimal pharmacotherapy. Both clinical and pharmacological considerations are accounted in order to promote rational pharmacotherapy, both in terms of efficacy and tolerability.

Expert opinion: Despite its clinical burden and relatively frequent occurrence, the interplay of MS and depression still requires further controlled trials to better clarify the appropriate pharmacotherapy across varying ‘diseases categories’ of MS itself, as well as discriminating between depressive symptoms that do not necessarily reach the threshold of either MDD or BD. Additional insight into new mood-tolerated neurological pharmacotherapy for MS is likewise warranted toward a more effective, immune- and patient-tailored pharmacotherapy, while promoting innovation in drug design, with the ultimate goal of enhancing the overall quality life of the affected individual, his/her caregivers, and to reduce the associated economic and social burden.     

多发性硬化症新药Tecfidera的药理与临床研究

富马酸二甲酯(BG-12)于2013年被美国FDA批准用于治疗成人复发型多发性硬化症(multiple sclerosis,MS),可能通过细胞保护和抗炎作用在复发缓解型多发性硬化症患者中发挥疗效。本文通过文献检索,对其药理作用、药动学、药物相互作用、临床研究和安全性进行了综述。     

多发性硬化的治疗的进展

多发性硬化(MS)的发病机制尚未完全明确,目前认为是由T细胞介导的一种自身免疫性疾病.而免疫干预治疗成为最重要的治疗手段,本文对MS的多种临床免疫治疗进展作一介绍.     

多发性硬化的治疗进展

多发性硬化是发生于中枢神经系统的由免疫介导的慢性自身免疫性脱髓鞘疾病。本病病因不明,可能与病毒感染和自身免疫功能紊乱等有关。其治疗方案仍不十分成熟,本文将主要从免疫干预治疗、基因治疗、干细胞移植治疗和其他治疗等四个方面对该病的治疗进展作一综述。     

Glatiramer acetate in the treatment of multiple sclerosis

This review article summarises the initial preclinical studies as well as the different stages of clinical trials in multiple sclerosis (MS) with Copolymer 1 (Cop 1), recently denoted glatiramer acetate. Experimental studies on autoimmune encephalomyelitis (EAE), the animal model of MS, as well as studies on the mechanism of action in both animals and humans are discussed. The review describes the early clinical trials which were followed by Phase II and III trials, culminating in FDA approval in 1996 for the treatment of relapsing-remitting MS. The accumulated experience with glatiramer acetate indicates that its efficacy is apparently increased as a function of usage time while the favourable side effect profile is sustained. MRI studies revealed that treatment with glatiramer acetate resulted in a significant reduction of gadolinium (Gd)-enhancing lesions. Ongoing clinical trials which might extend its usage or change its mode of delivery are also described. Glatiramer acetate appears to be a treatment of choice for the relapsing-remitting type of MS.     

Glatiramer acetate in the treatment of multiple sclerosis

This review article summarises the initial preclinical studies as well as the different stages of clinical trials in multiple sclerosis (MS) with Copolymer 1 (Cop 1), recently denoted glatiramer acetate. Experimental studies on autoimmune encephalomyelitis (EAE), the animal model of MS, as well as studies on the mechanism of action in both animals and humans are discussed. The review describes the early clinical trials which were followed by Phase II and III trials, culminating in FDA approval in 1996 for the treatment of relapsing-remitting MS. The accumulated experience with glatiramer acetate indicates that its efficacy is apparently increased as a function of usage time while the favourable side effect profile is sustained. MRI studies revealed that treatment with glatiramer acetate resulted in a significant reduction of gadolinium (Gd)-enhancing lesions. Ongoing clinical trials which might extend its usage or change its mode of delivery are also described. Glatiramer acetate appears to be a treatment of choice for the relapsing-remitting type of MS.     

格拉泰咪尔治疗复发-缓解型多发性硬化

格拉泰咪尔(GA)是合成的多肽化合物,其通过非特异性免疫调节作用、中枢神经内的旁观者抑制作用、作用于CD4~+CD25~+和CD8~+的调节性T细胞以及促进神经营养因子释放等机制调节免疫网络,使多发性硬化(MS)趋于缓解和修复。临床试验发现在复发缓解型MS(RRMS),GA治疗可减少临床复发、MRI所见的亚临床复发和延缓进展。其安全性好,长期治疗的疗效稳定。在RRMS治疗中一些作用机制优于干扰素,且临床研究发现的确在一些方面优于干扰素。基于这些,GA成为RRMS的一线治疗药物。     

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.     

Drugs treatment of pain in multiple sclerosis

Pain is a frequent and disabling symptom among multiple sclerosis (MS) and it is estimated to occur in 55% to 65% of patients. The mechanism of pain in MS has not yet been defined, because it can result from somatic, visceral, emotional, or neurologic impairment. The importance of this classification is related to different medical approaches to treat the pain in MS patients. In the management of symptomatic pain, new therapeutic strategies are now available to represent a great opportunity improving the quality of life. The availability of newer drugs for symptomatic treatment of pain in MS indicates a need to pay attention to this problem.     

New methods for multiple sclerosis drug discovery

Introduction: MS is a heterogeneous disorder that requires the development of better diagnostics to identify disease subtypes enabling appropriate therapeutic intervention at an early stage of the disease. Accumulating evidence indicates that members of the inhibitor of apoptosis (IAP) family play an important role in the pathogenesis of MS by reducing the apoptotic elimination of autoreactive immune cells. Areas covered: The authors describe improved animal modeling strategies to identify compounds that have immunomodulatory, neurorestorative and neuroprotective properties. In addition, the authors propose new approaches to better model cognitive dysfunction in MS, which will aid the development of novel therapeutics for this complex disorder. The paper provides the reader with an appreciation for the diagnostic and therapeutic potential of apoptosis-related proteins for MS. Expert opinion: Recent evidence suggests that increased resistance of autoreactive immune cells to apoptotic elimination is a contributing factor to both disease susceptibility and progression in MS. This occurs, at least in part, because of elevated levels of the IAP family of anti-apoptotic genes that display distinct expression profiles associated with different subtypes of MS. The authors believe that the detection and targeting of members of the IAP family can provide better drugs for MS. Particularly, the authors feel that the overexpression of IAPs in animal models can provide novel insights into MS for both its pathogenesis and the discovery of new lead compounds.     

New methods for multiple sclerosis drug discovery

Introduction: MS is a heterogeneous disorder that requires the development of better diagnostics to identify disease subtypes enabling appropriate therapeutic intervention at an early stage of the disease. Accumulating evidence indicates that members of the inhibitor of apoptosis (IAP) family play an important role in the pathogenesis of MS by reducing the apoptotic elimination of autoreactive immune cells.

Areas covered: The authors describe improved animal modeling strategies to identify compounds that have immunomodulatory, neurorestorative and neuroprotective properties. In addition, the authors propose new approaches to better model cognitive dysfunction in MS, which will aid the development of novel therapeutics for this complex disorder. The paper provides the reader with an appreciation for the diagnostic and therapeutic potential of apoptosis-related proteins for MS.

Expert opinion: Recent evidence suggests that increased resistance of autoreactive immune cells to apoptotic elimination is a contributing factor to both disease susceptibility and progression in MS. This occurs, at least in part, because of elevated levels of the IAP family of anti-apoptotic genes that display distinct expression profiles associated with different subtypes of MS. The authors believe that the detection and targeting of members of the IAP family can provide better drugs for MS. Particularly, the authors feel that the overexpression of IAPs in animal models can provide novel insights into MS for both its pathogenesis and the discovery of new lead compounds.     

Laquinimod in the treatment of relapsing remitting multiple sclerosis

Introduction: Laquinimod is a new once-daily oral administrable agent, which is under investigation in a phase 3 clinical trial for relapsing remitting multiple sclerosis (RRMS) and in a phase 2 clinical trial for primary progressive MS (PPMS).

Areas covered: The pharmacokinetic, pharmacodynamic and the safety profiles of laquinimod are covered in this review. In preclinical studies, the ability to prevent both experimental autoimmune encephalomyelitis and experimental autoimmune neuritis has been demonstrated. Reduced cell infiltration, demyelination, axonal damage and a shift of T-helper cell responses have been shown. Accordingly, in human studies, a decrease of pro-inflammatory and an increase of anti-inflammatory cytokines have been measured and a significant reduction of disease progression and a decrease in brain volume loss has been demonstrated. During all clinical studies a favorable safety profile was observed for 0.6mg laquinimod. New information about cardiovascular events is prompting the discontinuation of higher dosing regimens in both ongoing trials.

Expert opinion: Laquinimod is a first in class oral agent with high potential to reduce disease progression in RRMS and PPMS. Owing to its favorable safety profile, a combination with 0.6mg laquinimod and other disease modifying therapies could be an option in future MS therapy.     

Interferon-beta 1b in the treatment of multiple sclerosis

Ever since IFN-beta1b was first approved for the treatment of relapsing-remitting multiple sclerosis (RRMS) in the US and Europe, other disease-modifying drugs have become available. Phase III clinical trials have shown the efficacy of IFN-beta1b in the treatment of RRMS and secondary progressive MS in that it can reduce the annual relapse rate as well as magnetic resonance imaging parameters of activity and progression. There is mounting evidence that the best time to initiate treatment is early in the course of the disease, and available data suggest that efficacy is sustained for at least 5 years. IFN-beta1b is safe and well tolerated, although there are adverse events such as the flu-like complex and skin reactions. In the face of a proportion of RRMS patients experiencing a poor response to the drug, other therapeutic approaches need to be considered.     

Current disease-modifying treatment of multiple sclerosis

The treatment era for multiple sclerosis began in 1993 with the approval of the first disease-modifying therapy. This changed the management of multiple sclerosis from treating acute exacerbations to focusing on preventive therapeutic options that lessen the risk for exacerbations, changes on magnetic resonance imaging, and disability as measured by the Expanded Disability Status Scale. Currently, there are 8 therapies approved to treat multiple sclerosis: beta-interferons (Avonex, Betaseron, Extavia, and Rebif), fingolimod (Gilenya), glatiramer acetate (Copaxone), mitoxantrone (Novantrone), and natalizumab (Tysabri). These agents will be reviewed including the pivotal trial data, mechanisms of action, and side effects. The timing of beginning therapy and selection of these agents must be individualized for each patient depending upon patient preference, tolerability, clinical and magnetic resonance imaging disease activity, and disease course. All of the current treatments are approved for relapsing disease. To date only the injectable agents, including interferons and glatiramer acetate, have been shown to be of benefit when started after an initial demyelinating event referred to as clinically isolated syndrome. Mitoxantrone was approved for progressive relapsing and secondary progressive multiple sclerosis, although its use is limited by potential risks such as cardiotoxicity and leukemia. Although these agents have made a significant impact on the treatment of multiple sclerosis, they are often only partially effective, so patients may continue to have disease activity. Multiple new agents are currently being tested in clinical trials and it is likely our treatment paradigms will change as more effective therapies become available.