Mechanism of action and evidence basis for currently available disease modifying therapies and those undergoing regulatory review
| Drug | Summary of clinical effect | Selected clinical trials | Proposed mechanism of action | Selected on-going clinical trials |
|---|---|---|---|---|
| IFNs and glatiramer | Reduce relapse frequency by approximately one-third | Comparison of IFN-B and GA REGARD11 BEYOND12 | Unknown but biological effects include altered expression of numerous IFN-induced gene products and markers eg, MHC Class I, Mx protein, 2′/5′-oligoadenylate synthetase, β2-microglobulin, and neopterin | Efficacy and safety of PEGylated IFN-B1a (NCT01337427, NCT01332019, NCT00906399) |
| Natalizumab | Reduced relapse frequency by 68% | AFFIRM13 SENTINEL14 (Risk of PML with β-IFN cotreatment) | α4-integrin blocker; blocks migration of leucocytes into the CNS | INFORMS—phase 3 trial in PPMS (NCT00731692) |
| Fingolimod | Up to 60% reduction in ARR | FREEDOMS15 Comparison with IFN-B TRANSFORMS16 17 | Sphingosine-1-phosphate (S1P) receptor blocker; retains T and B cells in secondary lymphoid tissue | Longer-term safety and efficacy study in RRMS (NCT00670449) INFORMS efficacy in PPMS (NCT00731692) |
| Dimethyl fumarate | Reduction in ARR against placebo (44–53%) | DEFINE placebo-controlled phase 3 CONFIRM Phase 3 study vs placebo and including GA as reference comparator | Activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) transcriptional pathway | Longer-term safety and efficacy study in RRMS (NCT00835770) |
| Teriflunomide | Approximately 30% reduction in ARR | TEMSO18 Safety study of cotreatment with IFN-B1a19 | Metabolite inhibits mitochondrial dihydroorate dehydrogenase with subsequent inhibition of proliferation and effector functions of B and T cells | TOWER—phase 3 vs placebo (NCT00751881) Comparison with IFN-B1a (NCT00883337) Efficacy of cotreatment with IFNB1a (NCT01252355) TOPIC—phase 3, efficacy in clinically isolated syndrome (NCT00622700) TENERE—phase 3, comparison with IFN-B1a (NCT00883337) TERACLES—phase 3 cotreatment with IFN-B vs IFN-B and placebo (NCT01252355) |
| Alemtuzumab | 55% improvement in number of patients relapsing over a 2-year period when compared against IFN-1Ba | CAMMS22320 Phase 2 study vs IFN-B1a CARE-MS I phase 3 study as 1st line vs IFN-1Ba21 CARE-MS II phase 3 study following 1st-line failure22 | Lymphocyte depletion with possible neurotrophic effects | Longer term extension studies in progress |
ARR, annualised relapse rate; GA, glatiramer acetate; IFN, Interferon; PML, progressive multifocal leucoencephalopathy; PPMS, primary progressive MS; RRMS, relapsing-remitting MS.