Advancements during the last decades have led to the recent approval of several oral drugs. In March 2019 for example the Food and Drug Administration approved cladribine tablets (Mavenclad) to treat relapsing forms of multiple sclerosis (MS) in adults, to include relapsing-remitting disease and active secondary progressive disease. These drugs are expected to gain in popularity and frequency of use at the expense of previously existing therapies. Further oral drugs are still under investigation, the most notable example being laquinimod, which was announced in August 2012 to be the focus of a third phase III trial after mixed results in the previous ones. Early trials of the female sex hormone estriol, led in part by Rhonda Voskuhl, have generated interest in reducing symptoms in women with RRMS. Similarly, several other studies are aimed to improve efficacy and ease of use of already existing therapies through the use of novel preparations. Such is the case the PEGylated version of interferon-β-1a, that has a longer life than normal interferon and therefore it is being studied if given at less frequent doses has a similar efficacy than the existing product. Peginterferon beta-1a was approved for use in the United States in August 2014. Preliminary data have suggested that mycophenolate mofetil, an anti-rejection immunosuppressant medication, might have benefits in people with multiple sclerosis. However a systematic review found that the limited evidence available was insufficient to determine the effects of mycophenolate mofetil as an add‐on therapy for interferon beta-1a in people with RRMS. Monoclonal antibodies, which are biological drugs of the same family as natalizumab, have also raised high levels of interest and<unk> . Alemtuzumab, daclizumab and CD20 monoclonal antibodies such as rituximab, ocrelizumab and ofatumumab have all shown some benefit and are under study as potential treatments for MS. Nevertheless, their use has also been accompanied by the appearance of potentially dangerous adverse effects, most importantly opportunistic infections. Related to these investigations is the recent development of a test against JC virus antibodies which might help to predict what patients are at a greater risk of developing progressive multifocal leukoencephalopathy when taking natalizumab. While monoclonal antibodies are probably going to have some role in the treatment of the disease in the future, it is believed that it will be small due to the risks associated to them. Another<unk>  strategy is to evaluate the combined effectiveness of two or more drugs. The main rationale for polytherapy in MS is that the involved treatments target different mechanisms of the disease and therefore, their use is not necessarily exclusive. Moreover, synergies, in which a drug potentiates the effect of another are also possible. Nevertheless, there can also appear important drawbacks such as antagonizing mechanisms of action or potentiation of deleterious secondary effects. While there have been several clinical trials of combined therapy none has shown positive enough effects to merit the consideration as a viable treatment for MS. Regarding neuroprotective and regenerative treatments such as stem cell therapy, while their<unk>  is considered of high importance at the moment they are only a promise of future therapeutic approaches. Likewise, there are not any effective treatments for the progressive variants of the disease. Many of the newest drugs as well as those under development are probably going to be evaluated as therapies for PPMS or SPMS, and their improved effectiveness when compared with previously existing drugs may eventually lead to a positive result in these groups of patients. Disease-modifying drugs Disease-modifying drugs represent possible interventions able to modify the natural course of the disease instead of targeting the symptoms or the recovery from relapses. Over a dozen clinical trials testing potential therapies are underway, and additional new treatments are being devised and tested in animal models. New drugs must pass several clinical trials in order to get approved by regulatory agencies. Phase III is normally the last testing phase and when results are as expected a formal approval request is submitted to the regulator. Phase III programs consist of studies on large patient groups (300 to 3,000 or more) and are aimed at being the definitive assessment of how effective and safe a test drug will be. It is the last stage of drug development and is followed by a submission to the appropriate regulatory agencies (e.g., European Medicines Agency (EMEA) for the European Union, the Food and Drug Administration (FDA) for the United States, Therapeutic Goods Administration (TGA) for Australia, etc.) to obtain approval for marketing. Treatment in MS phase III studies is usually two years per patient. Relapsing-remitting MS Currently there are several ongoing phase III trials, and there are also some drugs that are waiting for approval after finishing theirs. The following drugs, at least, are also in phase III (for a complete list see Multiple sclerosis drug pipeline): *Tovaxin (injectable) A vaccine against self T-Cells, which consist of attenuated autoreactive T cells. It is developed by Opexa Therapeutics, (previously known as PharmaFrontiers), and finished a phase IIb September 2008, failing its primary target though in March 2008 was still performing good. After several financial troubles, a phase III trial has been granted in 2011 Secondary progressive variants Relapsing-Onset variants (RO), even when they turn into progressive, have proved easier to treat than Progressive-Onset variants. Though difficult to treat, Secondary progressive and Progressive-Relapsing are easier to treat than PPMS. Only Mitoxantrone has been approved for them, but there is nothing for PPMS. At this moment several therapies are under<unk> : *Cyclophosphamide (trade name Revimmune) is currently in Phase III for secondary progressive MS. It was also studied for RRMS but the company does not pursue actively this path. After a 2006 study for refractory cases it showed good behaviour Later, a 2007 open label study found it equivalent to Mitoxantrone and in 2008 evidence appeared that it can reverse disability. *Simvastatin has shown brain atrophy reduction in secondary progressive MS. *Masitinib, a tyrosine kinase inhibitor, is in late-stage testing for the treatment of patients with secondary and primary progressive MS (PPMS). It is a twice-daily oral medication that targets mast cells and inhibits several biochemical processes.14 *Ibudilast: MediciNova, Inc., announced that MN-166 (ibudilast) has been approved for "fast track" development by the U.S. Food and Drug Administration (FDA) as of 2016, as a potential treatment for progressive multiple sclerosis (MS). Progressive MS in this case means both the primary progressive (PPMS) and secondary progressive (SPMS) forms of the disease. Treatment for Primary Progressive variants Most Progressive-Onset variants does not have any approved disease-modifying treatment currently. Some possible treatments have been published, such as methylprednisolone pulses or riluzole, and some reduction of spasticity was reported in a pilot Italian study on low dose naltrexone but there is nothing conclusive still. Currently, good results using the monoclonal antibody Ocrelizumab in primary progressive MS (PPMS) have put the focus into depleting B cells targeting CD20 proteins A Statin, Simvastatin (Zocor), has shown good results in progressive variants Also Masitinib and Ibudilast, mainly targeted to SPMS have recruited PPMS patients in their clinical trials with good results. Respect the etiological<unk> , a special genetic variant named rapidly progressive multiple sclerosis has been described. It is due to a mutation inside the gene NR1H3, an arginine to glutamine mutation in the position p.Arg415Gln, in an area that codifies the protein LXRA. Highly active relapsing remitting variant Highly Active Relapsing Remitting, sometimes called Rapidly Worsening relapsing remitting, is a clinical form considered distinct from standard RRMS during clinical trials, being normally non responsive to standard medication. As of 2011, fingolimod has been approved as the first disease modifying therapy for this clinical course. Cyclophosphamide is currently used off-label for Rapidly Worsening MS (RWMS). Pediatric MS Pediatric patients constitute a particularly interesting MS population since the clinical onset of the disease is likely very close to the biological one. Therefore, this population offers the possibility of studying the MS pathogenesis closer to its root. Great Matter Lesions were observed in the cerebellum of almost all (93.3%) adolescents with pedMS and significantly outnumbered WML, suggesting that the cerebellar cortex is a main target of MS-related pathology in teens. A former problem with pediatric patients is that some variants of anti-MOG disease were considered MS before 2016. Therefore, publications before this date have to be considered with caution. Currently the only approved treatment for pediatric MS is fingolimod.
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Multiple sclerosis drug pipeline
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Multiple sclerosis functional composite
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