INDIVIDUAL DRUGS (from earliest to latest)
Beta interferons(Avonex, Betaferon, Extavia, Plegridy, Rebif) 1993
Mechanism: Beta interferons are a group of immunmodulators, but the exact mechanism of action is not fully understood. They do act via cytokines, interleukin, and IF-gamma inhibition. Indications: First line treatment in an active RRMS and SPMS. Dose: Avonex: 30mcg/week I/M by autojection pre-filled syringes. Betaferon: 250mcg every other day S/C by autoject pre-filled syringes. Plegridy(Peginterferon-beta1 A), comes in pre-filled pen. At 0 time:63mcg, day 14: 94mcg, day 28 and after 125mcg every two weeks. Plegridy is now permitted in pregnancy if indicated.
Glatiramer Acetate(Copaxone) 1996
Mechanism: GA is a polymer of amino acids, and it has a complex modes of action which are still not understood fully. However, cellular immune responses are shifted from inflammatory to anti‐inflammatory cytokines. This T helper type 1 (Th1) to Th2 shift seems to be responsible for some of the effects. Other mechanisms are inhibition of activation and proliferation of encephalitogenic T cells and a modulation of antigen‐presenting cells. Brain‐derived neurotrophic factor production is increased in response to GA treatment. BDNF may possess neuroprotective capacity, as it may play an important role in the protection of axons. Indication: First line treatment for RRMS. Dose: 20mg/day S/C injections using autoject ready-made doses. Also, 40mg 3/week is available by autoject. Monitoring: Initial investigations as per clinic practice, but no regular investigations then required. Pregnancy: No teratogenic effects reported in animal trials. Pregnancy safety category B. Copaxone should be used during pregnancy only if clearly needed.
Mitoxantrone(Novantrone) 2000
Natalizumab(Tysabri) 2004
Alemtuzumab(Letrada) 2007
Fingolimod(Gilenya) 2010
Mechanism: Fingolimod is a sphingosine-1-phosphate receptor agonist. It leads to a reduction in the number of circulating lymphocytes by preventing their migration from secondary lymph organs, but it does not alter T-cell activation or proliferation. Indications: NICE In England & Wales approved Gilenya to be used as a second line DMT in a highly active disease on at least one other DMT, or in a rapidly evolving RRMS on other DMTs. Dose: 0.5mg tablets orally/day. Monitoring:
Teriflunomide (Aubagio) 2012
Mechanism: Teriflunomide is the active metabolite of leflunomide. It is an immunomodulator with anti-inflammatory properties that reversibly inhibits dihydroorotate dehydrogenase, a key mitochondrial enzyme involved in pyrimidine synthesis for DNA replication. Although the exact mechanism by which teriflunomide exerts its therapeutic effects in MS is not fully understood, it is thought to be mediated by a reduced number of lymphocytes. Indications: RRMS. Not for highly active MS. Dose: 14mg, Orally, once daily. Monitoring: Before starting therapy- Exclude pregnancy. Obtain transaminase and bilirubin levels (within 6 months). Obtain a CBC (within 6 months). Screen for latent tuberculosis infection with a tuberculin skin or blood test. Check blood pressure. During therapy: Monitor ALT levels at least monthly for the first 6 months. Check blood pressure periodically. Adverse effects: The most frequent adverse reactions: Headache, ALT elevations, diarrhea, alopecia, and nausea. Pregnancy: Not allowed.
Dimethyl Fumarate (Tecfidera) 2013
Dimethyl fumarate is the methyl ester of fumaric acid. Dose: 120mg orally twice daily for one week, then 240mg twice daily to continue.
Daclizumab (Zinbryta) 2016
Biogen and AbbVie have announced the voluntary worldwide withdrawal of marketing authorisations for Daclizumab (Zinbryta) for the treatment of relapsing multiple sclerosis as a result of the “complex and evolving benefit/risk profile” including seven reported cases of inflammatory brain disorders (encephalitis and meningoencephalitis) associated with daclizumab. NICE in the UK, and the European Medicines Agency have already issued medical advises to stop this drug with an immediate effect. All patients who are on this treatment will be contacted by their neurologist to sort this matter for them in connection to this urgent matter.
Ocrelizumab (Ocrevus) 2017
Ocrelizumab is a humanised monoclonal antibody designed to target CD20-positive B-cells, which are implicated in the inflammatory and neurodegenerative processes of multiple sclerosis. NICE: Ocrelizumab is currently approved for RRMS, and is also approved in USA and parts of Europe for PPMS, but not yet in UK.
Cladribine (Mavenclad) 2017
Mechanism: It is probably the best oral DMT so far. It has a novel mechanism of action by directly reconstitute the immune system instead of suppressing it. It does reduce the lymphocytes initially, but the recovery of lymphocytes takes place by producing new unsensitised lymphocytes which are resistant to external stimulation for them to avoid enhancing MS activity. This mechanism of action is really novel, and none of the currently available DMTs for MS has a similar mechanism of action. The drug is very effective with rare side effects, has a very low monitoring programme, and pregnancy is allowed safely after 18 months of the first day of treatment. Indications: Highly active RRMS. Dosage:The dosage is very much individual depending on body weight. Total dosage is calculated as 3.5mg/Kg body weight, and given as 10mg or 20mg/day for 4 or 5 days, then the same after 4 weeks. The same treatment is repeated in 12 months in exactly the same way. No more treatment is required after that. Monitoring: The least monitoring programme among all recent DMTs. 3 blood tests in the first year(before treatment, 3, and 7 months after), and the same on the second year. No more monitoring is required unless the lymphocyte count is less than 0.5 x 109/L which is rare. Adverse effects: Generally very rare. Pregnancy: Allowed safely after 18 months from the start of treatment.
OZANIMOD(Zeposia) 2020
Ozanimod is an oral agent, now approved for an active RRMS. It is used once daily, and camn be used as naive or switch/escalating treatment.
OFATUMUMAB(Kesimpta) 2021
Ofatumumab is a targeted, precisely dosed and delivered B-cell therapy that provides the flexibility of self-administration for adults with RMS. It is an anti-CD20 monoclonal antibody (mAb) self-administered by a once-monthly injection, delivered subcutaneously. Initial loading doses of Ofatumumab are given at Weeks 0, 1 and 2, with the first injection performed under the guidance of a healthcare professional.
Ofatumumab is a monoclonal antibody thought to work by binding to a distinct epitope on the CD20 molecule inducing potent B-cell lysis and depletion. The selective mechanism of action and subcutaneous administration of this agent allows precise delivery to the lymph nodes, where B-cell depletion in MS is needed, and preclinical studies have shown that it may preserve the B-cells in the spleen. Once-monthly dosing also allows faster repletion of B-cells and offers more flexibility.