Teriflunomide for multiple sclerosis
Abstract
Background
Disease‐modifying therapies (DMTs) for multiple sclerosis aim to specifically reduce inflammation in relapsing multiple sclerosis and promote neuroprotection and neurorepair in progressive multiple sclerosis (MS). Most of the currently available disease‐modifying drugs (DMDs) require regular and frequent parenteral administration, which imposes a burden on patients and leads to reduced adherence. Not all MS patients respond adequately to current DMDs and, therefore, alternative MS treatments with less invasive routes of administration and new modes of action are required to expand the current treatment repertoire, increase adherence, and thereby improve efficacy. As one of the oral DMDs, teriflunomide is a potentially promising new oral agent in the treatment of relapsing MS. It inhibits dihydro‐orotate dehydrogenase (DHODH) and the synthesis of pyrimidine and has selective immunosuppressive and immunomodulatory properties.
Objectives
To explore the potential benefits of teriflunomide and so expand the available DMT options, the effectiveness and safety of teriflunomide, as monotherapy or combination therapy, were assessed versus placebo or approved DMDs (IFN‐β, glatiramer acetate, natalizumab, mitoxantrone, fingolimod) for modifying disease in patients with MS.
Search methods
The Trials Search Co‐ordinator searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register (27 June 2012). We checked references in identified trials and manually searched the reports (2004 to June 2012) from neurological associations and MS societies. We also communicated with researchers participating in trials on teriflunomide and contacted Sanofi‐Aventis.
Selection criteria
All randomised, double‐blind, controlled, parallel clinical trials (RCTs) with a length of follow‐up of at least one year evaluating teriflunomide, as monotherapy or combination therapy, versus placebo or other treatments (IFN‐β, glatiramer acetate, natalizumab, mitoxantrone, fingolimod) for patients with MS. Titles and abstracts of the citations retrieved by the literature search were screened independently for inclusion or exclusion by two review authors. Any disagreement regarding inclusion was resolved by discussion or by referral to a third assessor if necessary.
Data collection and analysis
Two review authors independently extracted data and assessed trial quality. Disagreements were discussed and resolved by consensus among review authors. Principal investigators of included studies were contacted for additional data or confirmation of information.
Main results
Two studies involving 1204 people evaluated the efficacy and safety of teriflunomide 7 mg and 14 mg, alone or with add‐on IFN‐β, versus placebo for adult patients with relapsing forms of MS (relapsing‐remitting (RRMS), secondary progressive (SPMS) with relapse, and progressive relapsing MS (PRMS)) and an entry Expanded Disability Status Scale (EDSS) score of ≤ 5.5. Both studies had high attrition bias (26.8% and 36.4% attrition respectively). Teriflunomide 7 or 14 mg alone had potential benefits on reducing relapse rates, and alone or with add‐on IFN‐β was safe for patients with relapsing forms of MS in the short term. The most common adverse events included nasopharyngitis, headache, diarrhoea, fatigue, elevated alanine aminotransferase levels, nausea, hair thinning or decreased hair density, influenza, back pain, urinary tract infection, and pain in the arms or legs. Four ongoing trials were identified.
Authors' conclusions
We found low‐level evidence for the use of teriflunomide as a disease‐modifying therapy for MS, due to the limited quality of the available RCTs. We did not conduct meta‐analysis because of the clinical and methodological diversity of the included studies. Short‐term teriflunomide, 7 or 14 mg alone or with add‐on IFN‐β, was safe for patients with relapsing MS. Both teriflunomide 7 and 14 mg alone had potential benefits for patients with relapsing forms of MS. We are waiting for the publication of ongoing trials. RCTs with high methodological quality and longer periods of observation are needed to assess safety, disability progression, neuroprotection and quality of life.
PICOs
Plain language summary
Teriflunomide, a new oral therapy for multiple sclerosis (MS)
New disease‐modifying therapies (DMTs) with less invasive routes of administration and new modes of action are in development to expand the available DMT options and enhance adherence, thereby improving efficacy. Teriflunomide is an oral disease‐modifying drug with immunosuppressive and immunomodulatory properties.The authors of this review assessed the efficacy and safety of teriflunomide in patients with different forms of MS (relapsing‐remitting (RRMS), secondary progressive (SPMS) with relapse, and progressive relapsing MS (PRMS)). They took into account the annualised rate of relapse, the proportion of patients free of disability progression, and the number of brain lesions. Among the pertinent literature, two studies met the inclusion criteria. They involved a total of 1204 patients and evaluated the efficacy and safety of teriflunomide alone or with add‐on IFN‐β, respectively, versus placebo. The authors were unable to give any clear recommendations for the use of teriflunomide as a DMT for MS because the studies had limited quality, were of short duration and were funded by a pharmaceutical company. As far as safety is concerned, common adverse events included headache, diarrhoea, fatigue, elevated alanine aminotransferase levels, nausea, hair thinning or decreased hair density, influenza, and urinary tract infection. Future studies are needed with higher methodological quality, a better evaluation of the adverse events, and a longer period of teriflunomide administration.
