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 an MS 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.
, the approved drugs for relapsing-remitting MS (RRMS) are:
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)
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.
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.
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.
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:
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 do not become 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:
Research into progressive variants.
Progressive variants are more difficult to treat than the Relapsing-Remitting course. Normally research for PPMS and SPMS go together, being more difficult to treat PPMS. This section presents research on SPMS, with mentions of PPMS where applicable.
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 most of the previous pipeline drugs have been or will be tried on it at some point. At this moment several therapies are under research:
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
Combined therapies.
Several combinations of drugs have been tested. Some of them are couples of approved drugs. Other tests try one approved drug with one experimental substance. Finally, at some point there could appear some trials testing couples of non-approved drugs.
As of 2016, there are 10 active principles approved which are: Two interferons (interferon beta-1a and interferon beta-1b), glatiramer acetate, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate and finally three monoclonal antibodies (natalizumab, alemtuzumab and since May 2016 daclizumab)
Summary table.
Summarizing in a table which combinations have been tried:
Biomarkers for the expected response.
Personalized treatment or theranostics in MS is an active field or research. Currently is trying to predict the response to the different known medications.
Interferons.
Beta-interferons are contraindicated in cases of anti-AQP4 or anti-MOG seropositivity. Interferon injections can induce neutralising antibodies against them, turning the medication ineffective. IFN-β 1b is more immunogenic than IFN-β 1a, and the subcutaneous administration has a higher risk than the intramuscular administration Both interferons should induce MxA (myxovirus protein A) mRNA, being its absence a negative indicator
There is heterogeneity in the immunologic pathways even restricted to RRMS population, and it correlates with IFN-β response. In a small study patients were clustered into 6 distinct subsets by baseline cytokine profiles. Two subsets were associated with patients who responded poorly to therapy. Two other subsets showed a significant reduction in relapse rates and no worsening of disability.
Glatimer Acetate.
For Glatimer Acetate, the biomarkers for response are interleukins. IL-27 is a biomarker for response, and IL-18 and IL-4 are also possible good biomarkers
It also seems that phosphorylated SIRT1 expression in mRNA is also a biomarker for response.
Mitoxantrone.
The best predictive biomarker for Mitoxantrone available is the number of relapses in separate areas within the past 24 months before treatment.
Natalizumab.
Natalizumab can also induce neutralising antibodies 4 to 6 months after treatment initiation. Fetuin-A (alpha-2-HS-glycoprotein) and circulating CD49 expression are emerging biomarkers for the therapeutic efficacy of natalizumab.
Fingolimod.
Lymphocyte subpopulations in peripheral blood is a promising tool to select RRMS candidate for fingolimod treatment.
Rituximab and anti-CD20.
Gadolinium enhancement before treatment initiation as a predictor of anti-CD20 response in MS.