title: The Use of Oral Disease-Modifying Therapies in Multiple Sclerosis.
abstract: Three oral disease-modifying drugs-fingolimod, teriflunomide, and dimethyl fumarate (DMF)-are available for treatment of relapsing forms of multiple sclerosis (MS). All three agents were approved in the last decade, primarily on the basis of a moderate to substantial reduction in the occurrence of MS relapses and central nervous system lesion formation detected by MRI. In the trials leading to approval, the first oral disease-modifying drug, fingolimod, reduced the annualized relapse rate (ARR) from 0.40 in placebo-treated patients to 0.18 (FREEDOMS) and from 0.33 in patients treated with interferon β1a intramuscularly to 0.16 (TRANSFORMS). Teriflunomide, approved on the basis of the two placebo-controlled trials TEMSO and TOWER, demonstrated a reduction in the ARR from 0.54 to 0.37 and from 0.50 to 0.32 respectively. The latest oral MS medication, approved in 2014, is DMF, which had been used in a different formulation for treatment of psoriasis for decades. In the 2-year DEFINE study, the proportion of patients with a relapse was reduced to 27 %, compared with 46 % in placebo arm, whereas in the CONFIRM trial, the ARR was reduced from 0.40 (placebo) to 0.22 in the DMF-treated group of patients. In this review, we will elucidate the mechanisms of action of these three medications and compare their efficacy, safety, and tolerability as a practical guideline for their use. We will further discuss effects other than relapse reduction these small molecules may exert, including potential activities within the central nervous system, and briefly summarize emerging data on new oral MS drugs in clinical development.
authors.affiliation: Department of Neurology, University Medical Center, 37075, Göttingen, Germany.|Doctor's Office Knaak/Christmann/Wüstenhagen of Neurology and Psychiatry, 34346, Hann. Münden, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Kretzschmar
authors.affiliation: Department of Neurology, University Medical Center, 37075, Göttingen, Germany.|Institute of Neuropathology, University Medical Center, 37075, Göttingen, Germany.
authors.forename: Hannah
authors.initials: H
authors.lastname: Pellkofer
authors.affiliation: Department of Neurology, University Medical Center, 37075, Göttingen, Germany. martin.weber@med.uni-goettingen.de.|Institute of Neuropathology, University Medical Center, 37075, Göttingen, Germany. martin.weber@med.uni-goettingen.de.|Department of Neuropathology, Department of Neurology, University Medical Center, Georg August University, Robert-Koch-Str. 40, 37099, Göttingen, Germany. martin.weber@med.uni-goettingen.de.
authors.forename: Martin S
authors.initials: MS
authors.lastname: Weber
mesh_terms: D000818:Animals; D002986:Clinical Trials as Topic; D003437:Crotonates / Q000627:therapeutic use*; D000069462:Dimethyl Fumarate / Q000627:therapeutic use*; D000068876:Fingolimod Hydrochloride / Q000627:therapeutic use*; D006801:Humans; D006885:Hydroxybutyrates; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D009103:Multiple Sclerosis / Q000188:drug therapy*; D009570:Nitriles; D015363:Quinolones / Q000627:therapeutic use*; D014052:Toluidines / Q000627:therapeutic use*
chemical_list: D003437:Crotonates; D006885:Hydroxybutyrates; D007166:Immunosuppressive Agents; D009570:Nitriles; D015363:Quinolones; D014052:Toluidines; C527525:teriflunomide; C476223:laquinimod; D000069462:Dimethyl Fumarate; D000068876:Fingolimod Hydrochloride
keywords: Dimethyl fumarate; Disease-modifying therapy; Fingolimod; Laquinimod; Multiple sclerosis; Teriflunomide