Multiple sclerosis drug pipeline

Since a theoretical model of the disease is hypothesized, until a drug appears that interferes with one of its pathways, several phases must be completed. First an animal model of the pathway to be studied must be developed, and the possible drugs that will be tried to interfere with it must be tried out. After that, three phases of human testing begin, and if everything works as expected, finally the drug will reach the status of approved by the regulatory agencies.

Approved medication

As of 2016, there are 10 active principles approved for RRMS and one for SPMS. Currently there is nothing approved for PPMS.

The approved drugs for RRMS are: Two interferons (interferon beta-1a and interferon beta-1b), glatiramer acetate, mitoxantrone, teriflunomide,[1] dimethyl fumarate,[2] one S1P modulator (fingolimod) and finally three monoclonal antibodies (natalizumab, alemtuzumab[3] and since May 2016 daclizumab[4][5]).

Only one of them, Mitoxantrone, has been approved for Secondary Progressive MS (SPMS) and for the special course of PPMS "rapidly progressive multiple sclerosis".[6] There is no disease-modifying treatment for normal Primary Progressive (PPMS), but currently several new drugs are being tried out in clinical trials.

Cleared for review and fast track

When a company considers that there is enough information from clinical trial to fill an application, they submit to the regulatory agencies a request for approval. When the agency considers that the request is worthy to be evaluated they grant the state "under review" to the drug. Some regulatory agencies have special workflows for drugs that cover something uncovered, like the FDA fast track.

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 (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 2 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 may work 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.

Research into progressive variants

Progressive variants are more difficult to treat than the Relapsing-Remitting course. Normally research for PPMS and SPMS goes together, being more difficult to treat PPMS. Therefore, we present here the research on SPMS with a mention to PPMS when 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[53]

Other possible treatments under research

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,[1] dimethyl fumarate[2] and finally three monoclonal antibodies (natalizumab, alemtuzumab[3] and since May 2016 daclizumab[4][5])

Combination of approved drugs

Approved and experimental drugs combined

Summary table

Summarizing in a table which combinations have been tried:

Interferon beta-1a Interferon beta-1b (Betaseron) Glatiramer acetate (Copaxone) Mitoxantrone Natalizumab (Tysabri) Fingolimod (Gilenya) Teriflunomide (Aubagio) Dimethyl fumarate BG12 (Tecfidera) Alemtuzumab (Lemtrada)
Interferon beta-1a
Interferon beta-1b (Betaseron) NO
Glatiramer acetate (Copaxone) YES[98] NO
Mitoxantrone NO NO YES[91][92]
Natalizumab (Tysabri) YES (linked to PML) NO YES[93] NO
Fingolimod (Gilenya) NO NO NO NO NO
Teriflunomide (Aubagio) NO NO NO NO NO NO
Dymetyl fumarate BG12 (Tecfidera) NO NO NO NO NO NO NO
Alemtuzumab (Lemtrada)[111] NO NO NO NO NO NO NO NO
Atorvastatin (Lipitor) YES YES[105] NO NO NO NO NO NO NO
Cyclophosphamide NO YES NO NO NO NO NO NO NO
Inosine YES[107][108] NO NO NO NO NO NO NO NO

Biomarkers for the expected response

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[112] Both interferons should induce MxA mRNA, being its absence a negative indicator[113]

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[114][115]

The best predictive biomarker for Mitoxantrone available is the number of relapses in separate areas within the past 24 months before treatment.[116]

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[112]

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