multiple sclerosis drug pipeline multiple sclerosis drug pipeline there are several ways for pharmaceuticals for treating multiple sclerosis (ms) to reach the market. novel pharmaceuticals cannot enter the us market without fda approval, which typically requires evidence of safety and efficacy in human trials and large fees be submitted to the fda and found to be adequate. pharmaceuticals already on the market, such as vitamin d do not have to and may never have had do so, and the financial incentives to do so are relatively insignificant. thus lack of approval of such drugs implies neither efficacy nor lack of efficacy. in general, novel pharmaceuticals cannot enter a market without government approval; standards and political influences vary. approved medication the typical path to approval in the 21st century may include basic research leading to understanding of mechanisms of disease progression and prevention such as chemical pathways, and/or candidate medications that aid or interfere with such pathways, which may be tested in vitro or in an animal model. later, three typically sequential phases of testing in humans are common. promising results regarding safety, efficacy and side effects are generally needed at each major phase of development. usually the regulatory agencies approve a multiple sclerosis medication for a specific clinical course. treatments for rrms (relapsing-remitting), spms (secondary progressive) or ppms (primary progressive) are common. some times they approve it for a subtype, like highly-active ms (hams, inside rrms), rapidly-worsening ms (rwms, inside ppms) or "active spms" (previous progressive-relapsing) approved for relapsing-remitting as of 2021, the approved drugs for relapsing-remitting multiple sclerosis (rrms) are: two interferons: beta-1a and beta-1b (injections) three generic immunomodulators: glatiramer acetate (copaxone, injection) teriflunomide (aubagio), monomethyl fumarate itself and its two precursors, which alters the nrf2 (nuclear factor erythroid 2(nf-e2)-related factor 2) transcription factor: dimethyl fumarate (tecfidera), diroximel fumarate (vumerity), approved by the fda in october 2019. active principal monomethyl fumarate itself, (bafiertam), approved in april 2020. four s1p modulators: fingolimod (gilenya), an oral treatment and the first oral therapy approved for multiple sclerosis. siponimod (mayzent), oral. approved in march 2019 for cis, rrms and spms ozanimod: oral. it was approved by the fda in march 2020 with the trade name zeposia ponesimod (ponvory) five monoclonal antibodies: alemtuzumab (lemtrada, campath). natalizumab (tysabri) ocrelizumab (ocrevus) which is also approved for primary progressive (ppms) ofatumumab (kesimpta) is another anti-cd20 monoclonal antibody. ublituximab was approved for medical use in the united states in december 2022, with the name briumvi, for relapsing forms, clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive. there are reports comparing these treatments in front of each other. restricting the research only to relapses, it seems that alemtuzumab is the most cost effective while anti-cd20 monoclonal antibodies (rituxan, ocrevus) have the better safety vs. efficacy profile approved for special courses the courses primary progressive (ppms) and secondary progressive (spms) are normally treated apart from rrms. besides, the regulatory agencies treat sometimes apart the cases aspms (active secondary progressive), nspms(non-active spms), hams (highly active) and rpms (rapidly progressive) primary progressive: ocrelizumab and mitoxantrone are the only approved drugs for ppms. the last with restrictions. secondary progressive (spms, nspms, non-active spms): ozanimod, cladribine and mitoxantrone are approved for spms. the last with restrictions. though approved for spms its profile is considered dangerous and is not always risk worthy cladribine was approved also for spms (secondary progressive) in europe in 2017 and by fda in april 2019 with the name mavenclad. active spms (aspms, formerly progressive-relapsing): in the us, the approval of cladribine includes active spms (aspms, spms with relapses) in its approval. also siponimod, ofatumumab and ublituximab are approved for this special course "active spms" highly active ms (hams): as of 2020, cladribine is the only drug specifically approved for hams. rapidly progressive ms (rpms): for aggressive ms or rapidly progressive multiple sclerosis only mitoxantrone is approved withdrawn medication daclizumab finally, after some reported deaths, it has been withdrawn by the regulatory agencies that had it previously approved. phase iii 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 (ema) 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. masitinib, anticancer drug that blocks cell replication and immune responses, it targets the innate immune system (mast cells and microglia) and has shown efficacy in the progressive courses. the appropriate pathway to put forward masitinib through the regulatory agencies, for the treatment of progressive forms of multiple sclerosis, is under study evobrutinib is a selective oral bruton's tyrosine kinase (btk) inhibitor that has been shown to inhibit b-cell activation both in vitro and in vivo. in phase iii. tolebrutinib, in phase iii but currently on hold. expected fda submission on 2024 simvastatin, a cholesterol-lowering statin, has shown good results in progressive variants. this has shown brain atrophy reduction in secondary progressive ms. this drug is under research for ppms and spms in phase iii. phase ii phase ii studies are performed on mid-sized groups of patients (20 to 300) and are designed to assess whether a drug works in the targeted disease area, as well as to continue earlier safety assessments obtained in healthy volunteers. treatment in ms phase ii studies is with 4–12 months usually shorter than in phase iii studies. amiselimod, s1p modulator amiloride (midamor) - midamor is a sodium channel blocker. it can stop sodium from entering the nerve cells, which in turn reduces the release of calcium. therefore, midamor could have a neuroprotective function in ms patients atl1102 (under development by teva and antisense therapeutics) is a second-generation antisense inhibitor of cd49d, a subunit of vla-4 (very late antigen-4). results of a phase iia have been reported. cdp323 (under development by ucb s.a. and biogen) is a compound for oral intake acting against α4-integrin, i.e., it has the same mechanism of action as natalizumab. phase ii investigations started in 2007. clemastine fumarate, also known as meclastin, is an antihistamine and anticholinergic drug. between jan 1, 2014, and april 11, 2015, it performed well in a phase ii clinical trial estradiol, estriol, and estrogen receptors(er): estrogens have been shown to be anti-inflammatory and neuroprotective in a variety of neurological disease models and it is known that they work also in presence of inflammation. research in this area has focused on the efficacy of estriol as a treatment to reduce symptoms of relapse-remitting multiple sclerosis in non-pregnant women. ibudilast: a phase ii trial shows that ibudilast does not reduce lesion rate, but prevents them to turn into black holes. they classify its action as class iii evidence of delay on disease activity in march 2016 ibudilast was designated a fda fast track candidate for progressive ms. anyway as of 2020 is still on phase ii. inosine: inosine is a compound that has shown interesting preliminary results in phase i and ii clinical trials. two different mechanisms of action have been proposed. first, it produces uric acid after ingestion, which is a natural antioxidant; second, it has been shown to induce axonal rewiring in laboratory animals with stroke, and spinal cord injury. however it can cause health problems in a long-term treatment, mainly kidney stones. it seems that its mechanism of action is peroxynitrite inactivation other reports point to an immune modulation stem cell transplantation was found feasible in a phase i/ii study in 21 patients with relapsing-remitting ms not responsive to interferon beta. it involves collecting some of the patient's own peripheral blood stem cells, giving low-intensity chemotherapy to eliminate auto-reactive lymphocytes, and then reinfusing the stem cells. earlier studies in the secondary-progressive stage of ms have failed to shown reversal of neurological symptoms. temelimab or geneuro gnbac1 - monoclonal antibody against the viral the herv-w envelope glycoprotein, which is supposed to be somehow pathogenic. it has passed a phase iib and a high dosis safety profile study in phase iib fluoxetine (prozac) riluzole (rilutek) orelabrutinib phase i and animal models phase i and medicaments used in animal models would make a huge list. here only some of them with special interest are listed. gift15 is a treatment which suppresses the immune system, and has been successfully used in the treatment of mice. the immune system attacks the central nervous system in multiple sclerosis patients. specifically a "granulocyte-macrophage colony–stimulating factor (gm-csf) and interleukin-15 (il-15) 'fusokine' (gift15) exerts immune suppression via aberrant signaling through the il-15 receptor on lymphomyeloid cells. we show here that ex vivo gift15 treatment of mouse splenocytes generates suppressive regulatory cells of b cell ontogeny (hereafter called gift15 breg cells)." bosentan, endothelin-1 antagonist, has been proposed to lower the et1 levels, which are involved in brain hypoperfusion carnosol, a natural compound found in rosemary, which has been found to prevent microglia activation metformin - a drug that reverses age-related (but also injury-related) changes in olegodendrocytes, making opcs respond to differentiation factors. first and second lines because of the side effects and dangers of some medications, they are classified into first and second line. first line includes the safest but less effective compounds, i.e. interferons and glatimer acetate. the second line includes the rest of the compounds and is usually a stronger medication. some ms organizations separate medications into three lines: moderately effective: teriflunomide (aubagio), beta interferons (1a and 1b) and glatiramer acetate. more effective: cladribine (mavenclad), dimethyl fumarate (tecfidera) and fingolimod (gilenya) highly effective: ocrelizumab (ocrevus) and natalizumab (tysabri) off and open label some compounds have regulatory (e.g. fda) approval, having been shown to be safe and effective for another purpose, however, they are not approved specifically for ms. this may be because of lack of funding to go through the approval process. some doctors prescribe them off-label or under the schema of open label research. examples of ms drugs used off label include: rituximab - monoclonal antibody against cd20. according to some sources it has a better efficacy vs. safety profile than most approved drugs. cyclophosphamide - strong immunosuppressor with conflicting evidence. low-dose naltrexone (ldn). filgrastim research into progressive variants progressive ms (ppms and spms) is more difficult to treat than rrms. relapsing-onset variants (ro), even when they turn into progressive ms, are easier to treat than progressive-onset variants. though difficult to treat, spms and progressive-relapsing ms are easier to treat than ppms. ocrelizumab has been approved for ppms and for active spms with relapses. mitoxantrone has been approved for them but is rarely used due to severe risks. several therapies are under research. cyclophosphamide (revimmune) is in phase iii trials for secondary progressive ms. it was also studied for rrms but the company does not pursue actively this path. in a 2006 study for refractory cases it showed some effectiveness a 2007 open label study found it equivalent to mitoxantrone and in 2008 evidence appeared that it can reverse disability. some ppms patients with a special biomarker (immunoglobulin m oligoclonal bands) have been shown to respond to standard rrms medications, though there is only preliminary evidence waiting to be confirmed other possible treatments under research antimicrobial agents against chlamydophila pneumoniae: ms patients are more likely to have detectable levels of chlamydophila pneumoniae dna in their cerebrospinal fluid, compared to other patients with neurological diseases; however these findings are insufficient to establish an etiologic relation. anecdotal reports of the use of antimicrobial agents against chlamydophila pneumoniae are favorable, but only one double-blind placebo-controlled trial has been published, in which the number of patients studied was too small (four in each arm of the trial) to reach statistical significance in the primary outcome measure (volume of gadolinium-enhancing lesions, as viewed on mri). antioxidants, available as supplements, are reported to reduce the blood–brain barrier permeability. related to this, ms patients have been reported to have low levels of uric acid, which is a natural antioxidant, and has been observed that raising uric acid levels protects against blood–brain barrier destruction (through peroxynitrite scavenging ). peroxynitrite has been correlated with the axons degeneration and its removal can protect neurons from further