Treatment of multiple sclerosis
The first disease-modifying therapy for relapsing–remitting multiple sclerosis — interferon‑β 1b — was approved by the FDA in 1993. The following 25 years have seen rapid expansion of the therapeutic options as an evolving understanding of the disease has enabled development of therapies with different modes of action. As a result, we now have a complex treatment landscape that includes various injectables, oral drugs and monoclonal antibodies, each of which has its own advantages and risks. This Milestone tracks the development of the treatment of multiple sclerosis on an interactive Timeline, from the approval of the first disease-modifying therapy to the latest breakthroughs that have seen unprecedented efficacy and approval of the first drug for primary progressive multiple sclerosis.
NR Neurology Reviews
The development of treatment for multiple sclerosis over the past 25 years is a success of translational medicine. In this Timeline article, Tintore et al. chart major developments and discuss the implications for current and future patient management.
In clinical trials, outcome measures might determine whether a drug is worthy of further development; in the clinic, they might guide important treatment decisions. Here, Tur and colleagues help clinicians and researchers navigate the maze of options for clinical, neuroimaging, patient-reported and composite outcome measures in multiple sclerosis.
The benefits of early treatment for multiple sclerosis (MS) place pressure on physicians to make the diagnosis early, thereby increasing the risk of misdiagnosis, which can have considerable consequences for patients and health-care systems. Solomon and Corboy examine the problem of MS misdiagnosis, including the probable causes and associated risks, and discuss how the tension between early diagnosis and misdiagnosis might be addressed.
Autologous haematopoietic stem cell transplantation has produced striking results in patients with aggressive multiple sclerosis in small trials. In this Review, Muraro et al. provide an overview of the procedure, detail evidence for its high efficacy in multiple sclerosis, and provide recommendations for its clinical use and future trials.
Real-world observational studies have the potential to answer questions about multiple sclerosis (MS) treatment that randomized controlled trials cannot. Trojano and colleagues discuss the pitfalls and necessary safeguards in observational studies, and the insights that such studies have provided into treatment decisions for patients with MS.
The range of immunomodulatory therapies to treat multiple sclerosis (MS) has widened markedly in recent years, and MS treatments have become more efficient. This improvement in efficacy has been accompanied by an increased risk of treatment-associated infections. In this Review, Winkelman et al. discuss the modes of action of the currently available MS therapies and detail the specific infections associated with each treatment. They consider how this information can influence the daily clinical use of MS therapies, so as to minimize the associated infectious risk.
In this Review, Mishra and Yong consider how myeloid cells — monocytes, macrophages, microglia and dendritic cells — contribute to the pathology of multiple sclerosis (MS). The authors also consider how current multiple sclerosis treatments might directly and indirectly affect these cells.
A subset of patients with multiple sclerosis (MS) demonstrate rapid accumulation of disability, and symptoms that are refractory to standard disease-modifying therapies. Rush and colleagues present criteria for identifying patients with so-called aggressive MS, and outline the efficacy of various therapies in this group of patients. The authors emphasize the need to act quickly with these patients, and propose a treatment algorithm to aid clinical decision-making.
As the range of therapeutic options for multiple sclerosis (MS) continues to expand, the ability to select the most appropriate treatment for each patient becomes increasingly important. In this Review, Sormani and De Stefano assess the studies that have attempted to classify patients with MS on the basis of their response to IFN-β treatment. The authors also discuss the development and use of scoring systems that combine different clinical and MRI markers to aid definition of an early response to this drug.
Increasing evidence supports a role for B cells and antibodies in the pathogenesis of multiple sclerosis (MS). Here, Meinl and colleagues discuss the proinflammatory contribution of B-cell signalling in MS, and consider potential targets of autoantibodies. The B-cell response to various MS therapies is also summarized.
Only moderately effective therapies are currently available for the treatment of multiple sclerosis (MS). New treatments for MS that have neuroprotective properties as well as anti-inflammatory effects are needed. Fingolimod could be one such potential treatment. In this article, Aktas et al. examine the underlying biological actions of this prospective new therapy, review the data from phase II and phase III oral fingolimod clinical trials and provide an update on the emerging field of sphingosine-1-phosphate receptor-mediated therapies for MS.
Additional Reviews and Research
Multiple sclerosis is characterized by the formation of demyelination lesions throughout the central nervous system, leading to neurological dysfunction. This Primer provides an overview of the immunopathology, diagnosis and management of multiple sclerosis.
In this Focus Review, Bar-Or and colleagues discuss the latest evidence that B cells play an important antibody-independent role in multiple sclerosis and the prospects this holds for therapeutic intervention.
Multiple sclerosis (MS) is an inflammatory autoimmune disorder affecting the central nervous system (CNS) and the most common cause of neurological disability in young adults.
Systematic screening of generic drugs for progressive multiple sclerosis identifies clomipramine as a promising therapeutic
Progressive multiple sclerosis is an inflammatory and degenerative disease of the central nervous system, for which effective treatment is lacking. The authors carry out a screen to identify orally available generic medications, and show that the antidepressant clomipramine reduces pathology in mouse models.
In September 2010, fingolimod (FTY720/Gilenya; Novartis) became the first oral disease-modifying therapy to be approved by the US Food and Drug Administration for relapsing–remitting multiple sclerosis. Brinkmann and colleagues describe its discovery and development, and how elucidation of its effects on sphingosine 1-phosphate receptors has improved the understanding of the biology of these receptors.
News and comment
Following on from a recent European Academy of Neurology guideline on pharmacological treatment of multiple sclerosis (MS), the American Academy of Neurology has issued an updated practice guideline on disease-modifying therapies (DMTs) for MS. The guideline provides 30 general recommendations for initiating, switching and stopping DMTs, and indicates future research directions.
The treatment of multiple sclerosis (MS) has evolved remarkably over the past 25 years. This progress has been enabled by advances in research, drug development and active engagement of the scientific community with regulatory authorities. However, an inconsistent approach to MS disease courses could have a negative impact on the drug development process.
A compelling need exists for a more reliable risk evaluation of natalizumab- associated progressive multifocal leukoencephalopathy (PML). A new report proposes a refined protocol that uses updated patient-based data and cumulative risk evaluation to provide an improved assessment of the annual risk of PML for patients positive for JC virus.
As yet, no clear strategy has been developed for discontinuation of disease-modifying therapy in multiple sclerosis. A recent observational study adds new information, but the most informative patient groups are still to be assessed comprehensively, and several questions need to be addressed in prospective studies.
Recently published findings from the ENDORSE study provide 5 years of randomized safety and efficacy data for two doses of dimethyl fumarate (DMF) in multiple sclerosis. The report complements results from the pivotal CONFIRM and DEFINE trials; however, postmarketing data from clinical practice is needed to complete the risk–benefit profile of DMF.
Fingolimod is approved for the treatment of relapsing–remitting multiple sclerosis (MS), and evidence suggests that it has neuroprotective effects. The recent INFORMS phase III trial in primary progressive MS demonstrated no beneficial effects of fingolimod on disability progression or whole-brain atrophy, but provides important information for future therapeutic development.
A new study has shown that both in patients with multiple sclerosis (MS) and in healthy controls, dopamine inhibits production of IL-17 and IFN-γ by peripheral blood mononuclear cells. The finding adds to previous evidence for the potential benefit of dopaminergic drugs in MS.
A randomized, double-blind, phase III trial of generic glatiramer acetate has shown equivalent efficacy and safety compared with the approved formulation, Copaxone. The impact of approval of generic glatiramer acetate, however, will mainly depend on the pricing of the drug.
A new study shows that in patients with multiple sclerosis who exhibit active disease despite disease-modifying therapy, a switch to fingolimod is more effective than continuation of IFN-β or glatiramer acetate for preventing relapses and worsening of disability. These data support the utility of treatment escalation to improve disease control.
The past decade of multiple sclerosis research has been marked by important advances in understanding the disease, a dramatic increase in the range of treatment options and a new spirit of data sharing in research for patient benefit. This progress has made personalized medicine in multiple sclerosis a realistic possibility.
Aggressive, refractory multiple sclerosis warrants unconventional therapy. A retrospective multicentre study assessed the effects of ablating the immune system, then reconstituting it using bone marrow derived stem cells. Though this particular regimen improved disability in some patients, others continued to relapse, perhaps indicating the treatment did not go far enough.
Results of the TOWER phase III trial confirm the efficacy of teriflunomide in relapsing–remitting multiple sclerosis (RRMS). With seven substances now approved for RRMS, individualized treatment for the inflammatory aspect of the disease is within reach, although many questions remain unanswered, particularly concerning the neurodegenerative aspect RRMS.
A recent multicentre study has assessed the risk of relapse in patients with multiple sclerosis who switched from natalizumab to fingolimod treatment. Despite such efforts, no effective exit strategy from natalizumab treatment has yet been demonstrated for these patients.
Results from two phase III trials show the potency of alemtuzumab—a T-cell and B-cell depleting antibody—in reducing clinical and paraclinical measures of disease activity in relapsing–remitting multiple sclerosis. The effects of this immunotherapeutic agent highlight the relevance of T lymphocytes in the early pathogenesis of disease.
Several oral drugs have been developed in recent years for treatment of relapsing–remitting multiple sclerosis. Two large phase III trials have now clearly demonstrated the clinical efficacy and good safety profile of oral dimethyl fumarate (BG12)—an anti-inflammatory and cytoprotective agent—in patients with this disease.
Patients with relapsing–remitting multiple sclerosis have been shown to benefit from disease-modifying treatments over prolonged periods. More focus should now be placed on monitoring the long-term evolution of this disease (making use of tools such as MRI), alongside the patients' response and adherence to such treatments.
This article discusses the impact of new drugs on the market for multiple sclerosis, including the recently approved immunomodulatory drug ocrelizumab and drugs in development such as sphingosine 1-phosphate receptor modulators and neurorestorative agents.