Teriflunomide: A Review in Relapsing–Remitting Multiple Sclerosis
Lesley J. Scott1

© Springer Nature Switzerland AG 2019

Abstract
Teriflunomide (Aubagio®) is a disease-modifying immunomodulatory drug with anti-inflammatory properties that selec- tively and reversibly inhibits the mitochondrial enzyme dihydro-orotate dehydrogenase, with consequent inhibition of de novo pyrimidine synthesis and reduced lymphocyte proliferation. Based on extensive evidence from randomized controlled trials (RCTs) and the real-world setting, oral teriflunomide is an effective and generally well tolerated treatment in patients with relapsing multiple sclerosis (MS), with these benefits maintained during long-term treatment (≥ 10 years) and no new safety signals identified. In pivotal RCTs in this patient population, teriflunomide provided significantly better efficacy than placebo (TEMSO and TOWER) and was as effective as interferon β-1a (TENERE) in terms of improvements in clinical out- comes (such as reduced annualized relapse rates, prevention of disability progression) and/or MRI-assessed disease activity measures. Albeit head-to-head trials would definitively establish the relative efficacy of oral disease-modifying therapies, given its convenient oral regimen and beneficial effects in reducing relapses and disease activity, teriflunomide remains an effective option for the management of relapsing–remitting MS (RRMS).

The manuscript was reviewed by: E. Bernitsas, Department of Neurology, Wayne State University, Detroit, MI, USA; S. de
Biase, Neurology Unit, Department of Experimental and Clinical Medical Sciences, University of Udine Medical School, Udine, Italy; F. Ladeira, Hospital de Egas Moniz, Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal.

 Lesley J. Scott [email protected]
1 Springer Nature, Private Bag 65901, Mairangi Bay, Auckland 0754, New Zealand
⦁ Introduction
Multiple sclerosis (MS) is a chronic inflammatory demyeli- nating disease of the CNS, with onset typically occurring in early adulthood [1, 2]. The majority (≈ 85%) of patients initially present with relapsing–remitting (RR) MS charac- terized by recurrent relapses and remissions of neurologi- cal symptoms. Although its exact aetiology is unknown, key triggers involve the complex interaction of genetic and environmental factors [1, 2]. MS is a treatable, but as yet incurable disease, with immunomodulatory or immunosup- pressive disease-modifying therapy (DMT) forming the cor- nerstone of long-term treatment ever since the introduction of the first DMT [subcutaneous interferon (IFN) β-1b] in the early 1990s [2]. DMT results in a reduction in relapse rate, disease progression and other clinical markers, including MRI-assessed lesions and brain atrophy [1, 2]. Until almost a decade ago, all DMTs for MS were administered paren- terally (e.g. IFNβ-1b, glatiramer acetate) and were associ- ated with the inherent limitations of parenteral drugs such as adherence (especially in patients with chronic conditions), injection-site reactions and the development of antibodies [1]. Over the last decade, several new targeted oral DMTs have been approved for use in MS (e.g. cladribine, dimethyl fumarate, fingolimod, teriflunomide) [1, 2]. These agents have differing mechanisms of action, safety considerations

and risks, permitting optimization of each individual’s treat- ment based on patient preference, comorbid disease and other factors [1, 2]
Teriflunomide (Aubagio®), the main active metabolite
of the disease-modifying anti-rheumatic drug leflunomide [3–5], is an immunosuppressive drug with anti-inflamma- tory properties that selectively and reversibly inhibits the mitochondrial enzyme dihydro-orotate dehydrogenase, leading to inhibition of de novo pyrimidine synthesis and consequently reduced proliferation of T lymphocytes [3–6]. Although the exact mechanism of action associated with its therapeutic effects in MS remains to be fully elu- cidated, evidence suggests that it may involve a reduction
in the number of activated lymphocytes in the CNS [3, 4, 6]. The pharmacological properties of teriflunomide have been extensively reviewed and are summarized in Table 1. This review, written from an EU perspective, focuses on the clinical use of oral teriflunomide in adult patients with RRMS.

Table 1 Overview of key pharmacological properties of teriflunomide

Pharmacodynamic properties [3–6]
Mechanism of Action Immunomodulatory drug with anti-inflammatory properties that selectively and reversibly inhibits the mitochondrial enzyme dihydro-orotate dehydrogenase, leading to inhibition of de novo pyrimidine synthesis and a subsequent cytostatic effect on proliferation of T lymphocytes

Exact mechanism of action for therapeutic effects in pts with MS is unknown, evidence suggests it may involve a ↓ in the number of activated lymphocytes in the CNS
Effects on immune system In preclinical studies: impairs formation of immunological synapse, ↓ release of IL-6, IL-8 and MCP-1 from monocytes, preferentially affects proliferation of high-activity T cells

In PL-controlled trials with teriflunomide 14 mg/day: the mean ↓ in lymphocyte counts was < 0.3 × 109 cells/L; ↓ occurred during the first 3 months and thereafter remained stable

Effects on renal tubular function In PL-controlled trials: relative to PL, teriflunomide recipients had a ↓ in serum uric acid levels of
20–30% and ↓ in serum phosphorous of ≈ 10%
Effects on cardiac electrophysiology Not associated with clinically significant corrected QT prolongation in a thorough QT study

Pharmacokinetic properties [3, 4]
General profile Median tmax attained within 1–4 h post-dose after multiple doses; absolute oral bioavailability (≈ 100%); extensively bound to plasma protein (> 99%), mainly to albumin; Vd 11 L after a single IV dose; esti- mated AUC accumulation ratio is ≈ 34-fold; steady-state concentration attained in ≈ 100 days

Unchanged teriflunomide is the major circulating moiety; primarily metabolized by hydrolysis, with oxidation being a minor pathway
Elimination occurs mainly by direct biliary excretion of unchanged drug, as well as renal excretion of metabolites; and can be enhanced using cholestyramine or activated charcoal (both ↓ concentration of teriflunomide by > 98% after 11 days); median elimination half-life ≈ 19 days (multiple 14 mg doses)

Specific populationsa No clinically relevant effects, based on age, gender, bodyweight and ethnicity

Severe renal impairment had no impact; therefore, no dosage adjustment required in pts with mild, mod- erate or severe renal impairment
Mild and moderate hepatic impairment had no impact; therefore, no dosage adjustment required in these pts; the drug is contraindicated in pts with severe hepatic impairment

Potential drug-to-drug interactionsa Potent CYP inducers and inducers of P-gp or BCRP transporters (e.g. rifampicin, carbamazepine, pheno- barbital, phenytoin, hypericum)b
CYP2C8 substrates (e.g. repaglinide, paclitaxel, pioglitazone), CYP1A2 substrates (e.g. caffeine, dulox- etine, theophylline, tizanidine) and OAT3 substrates (e.g. cefaclor, benzylpenicillin, ciprofloxacin, furosemide, cimetidine)b

BCRP substrates (e.g. methotrexate, topotecan, sulfasalazine) or OATPB1/B3 substrates (e.g. simvasta- tin, atorvastatin, pravastatin, repaglinide, rifampicin)b
Monitor international normalized ratio closely when warfarin and teriflunomide are coadministered

AUC area under the plasma concentration–time curve, BCRP breast-cancer resistance protein, IL interleukin, IV intravenous, MCP-1 monocyte- derived chemotactic protein 1, MS multiple sclerosis, OAT(P) organic anion transporter (polypeptide), P-gp P-glycoprotein, PL placebo, pts patients, tmax time to attain maximum plasma concentration, Vd volume of distribution, ↓ indicates decrease/d/s
aConsult local prescribing information for detailed information
bDrugs for which caution is recommended when considering concomitant administration with teriflunomide

⦁ Therapeutic Efficacy of Teriflunomide
⦁ In Randomized Controlled Trials
⦁ In Patients with Relapsing MS

The efficacy of oral teriflunomide in terms of improve- ments in clinical (TEMSO [7]; TOWER [8]; TENERE [9]) and MRI-assessed disease activity (TEMSO) outcomes in adults (aged ≥ 18 years) with a confirmed diagnosis of a relapsing form of MS (RMS) was established in large (n > 300 randomized), placebo- (TEMSO and TOWER; Sect. 2.1.1.1) and active comparator-controlled (vs. IFNβ-1a) [TENERE; Sect. 2.1.1.2], double-blind [7, 8] or
rater-blinded [9], multinational [7, 8] or multicentre [9], phase 3 trials, all of which have been extensively reviewed [3]. The long-term benefits of teriflunomide treatment were maintained during ≥ 10 years’ follow-up in a phase 2 extension study and phase 3 TEMSO and TOWER exten- sion studies (Sect. 2.1.1.1).
Although all of the phase 3 trials included a terifluno- mide 7 mg once daily group (a lower dosage approved in the USA [10]), this section only discusses results for the teriflunomide 14 mg group (i.e. the approved dosage in the EU [4], which is also approved in the USA [10]; Sect. 4). The duration of the core study was 108 weeks in TEMSO [7], and ≥ 48 weeks in TOWER (median duration of treat- ment 84 and 83 weeks in the teriflunomide 14 mg and placebo groups) [8] and TENERE (median exposure 64.2 and 60.1 weeks in the teriflunomide 14 mg and subcutane- ous IFNβ-1a group) [9]. In the TEMSO extension, patients randomized to teriflunomide 7 or 14 mg/day continued treatment at the same dosage and those randomized to
placebo were re-randomized to teriflunomide 7 or 14 mg/ day. In the TOWER extension, all patients received terif- lunomide 14 mg/day.
In the overall populations, the mean time from first MS symptoms was ≥ 7 years [7–9]. Key eligibility criteria were an Expanded Disability Status Scale (EDSS) score of ≤ 5.5 (mean score at baseline ≈ 2.7 [7, 8] and 2.1 [9]), and the occurrence of at least two clinical relapses within the past 2 years or one within the past year [7, 8]. Key exclusion cri- teria included clinical relapse within the past 30 [8, 9] or 60
[7] days, presence of other clinically relevant systemic dis- eases [7–9], pregnancy [7–9], and the use of IFNβ (IFNβ-1a [9]), glatiramer acetate, natalizumab, mitoxantrone or other immunosuppressant agents in the previous 3 months [8, 9].
⦁ Versus Placebo In TEMSO and TOWER [4], 91.5 and 97.5% of patients had RRMS, 4.7 and 0.8% had sec- ondary progressive MS with relapses, and 3.9 and 1.7% had progressive relapsing MS.
Relative to placebo, teriflunomide treatment significantly improved key clinical outcomes during the specified study periods in TEMSO [7] and TOWER [8], with teriflunomide recipients having a significantly lower adjusted annualized relapse rate (ARR) [primary endpoint], fewer recipients experiencing 3-month sustained disability worsening and more recipients being relapse-free (Table 2). In pre-speci- fied subgroup analyses, reductions in ARR and confirmed 3-month sustained disability worsening rates at week 108 in TEMSO favoured teriflunomide treatment across all sub- groups of patients, including by baseline demographics (age, gender, ethnicity), disease characteristics (EDSS strata, MS subtype), MRI parameters [gadolinium (Gd)-enhancing lesions, total lesion volume] and prior use of DMT [11]. Pooled data from TEMSO and TOWER supported the

Table 2 Efficacy of oral teriflunomide 14 mg/day in randomized, double-blind, multinational, phase 3 trials; trials in patients with relapsing forms of multiple sclerosis

Study Treatment
(no. of mITT pts)
ARR (no. of confirmed relapses/pt-year’ exposure)a
3-month sustained disability worseningb (% of pts) [HR; 95% CI]
Absence of relapse (% of pts) [HR; 95% CI]

TEMSO [7] TER (358) 0.37*** (RR 31.5%) 20.2*c [0.70; 0.51–0.97] 56.5**,d [0.72; 0.58– 0.90]
PL (363 0.54 27.3c 45.6d
TOWER [8] TER (370) 0.32**** (RR 36.3%) 15.8*,c [0.68; 0.47–1.00] 76.3****,d [0.63; 0.50–0.79]

PL (388) 0.50 21.0c 60.6d
The majority (≥ 91%) of pts had RRMS. Trials also included a TER 7 mg/day group; a non- approved dosage in the EU (not tabulated)
ARR adjusted annualized relapse rate, EDSS Expanded Disability Status Scale (higher scores = greater disability), HR hazard ratio, mITT modi- fied intent-to-treat, PL placebo, pt(s) patient(s), RR relative reduction, RRMS relapsing–remitting multiple sclerosis, TER teriflunomide
*p < 0.05, **p < 0.01, ***p < 0.001, ****p ≤ 0.0001 vs. PL
aPrimary endpoint. The mean number of relapses in the previous year was 1.3–1.4 and in the previous 2 years was 2.1–2.2 bIncrease from baseline of ≥ 1.0 in EDSS score (or ≥ 0.5 in pts with a baseline EDSS score of > 5.5) that persisted for ≥ 12 weeks cAssessed over 48 (TOWER) or 108 (TEMSO) weeks’ treatment
dAssessed over 108 (TEMSO) or 132 (TOWER) weeks’ treatment

efficacy of teriflunomide in terms of ARR and 3-month sus- tained disability worsening in subgroups of patients stratified by prior DMT (post hoc analyses) [12]. Based on pooled data from TEMSO and TOWER, teriflunomide treatment reduced 3-month sustained disability worsening relative to placebo when more stringent exploratory definitions of this outcome were used [13]. There were no significant between- group differences for mean changes in Fatigue Impact Scale (FIS) scores at week 108 in TEMSO [7] and at week 48 in TOWER [8], with minimal changes from baseline in FIS scores in any study group.
In post hoc analyses of TEMSO [14] and TOWER [15], compared with placebo, treatment with teriflunomide 14 mg/ day was associated with significant reductions in relapses with sequelae defined by an increase in EDSS-functional system score (both trials p ≤ 0.0021), relapses with seque- lae defined by investigators (both trials p ≤ 0.0004), relapses requiring hospitalization (both trials p ≤ 0.0155), and relapses requiring intravenous corticosteroids (both trials p ≤ 0.0003). Annualized rates of all hospitalization and the number of nights in hospital for relapse were also signifi- cantly (all p < 0.05 vs. placebo) reduced in the teriflunomide 14 mg group in both trials [14, 15].
The beneficial effects of teriflunomide on clinical out- comes were maintained during long-term treatment in the TEMSO (≤ 7 [16], ≤ 9 [17] or ≤ 11 [18] years’ follow-up) and TOWER (≤ 7 years’ follow-up [18]) extension studies and phase 2 extension study (≤ 8.5 [19] and ≥ 10 [20] years’ follow-up), as were the MRI-assessed beneficial effects on disease activity during ≤ 5 years’ follow-up in the TEMSO extension study [21]. For example, in the TEMSO extension study, the ARRs for all relapses, relapses requiring hospi- talization and relapses requiring intravenous corticosteroid use were 0.230, 0.061 and 0.197 relapses/patient-year’ (PY) exposure, respectively, in the teriflunomide 14 mg group during ≤ 11 years of follow-up (n = 466) [18]. At 96 weeks, teriflunomide recipients experienced significant improve- ments from baseline in cognitive functioning compared with placebo in the TEMSO core study (mean adjusted changes
− 0.022 vs. 0.073; p = 0.0435), as assessed using Paced Auditory Serial Addition Test (PASAT)-3 Z scores [21]. Cognitive function continued to improve during 5 years of teriflunomide 14 mg/day therapy, with slower rates of brain volume loss (BVL) during the initial 2 years’ treatment cor- relating with greater improvements in PASAT-3 scores dur- ing this 5-year period [21]. In a pooled analysis of TEMSO and TOWER, 3-month sustained disability worsening was stable or improved in most teriflunomide recipients during 5 years’ follow-up, irrespective of subgroup stratification by baseline characteristics (e.g. type of relapsing MS [22, 23], EDSS score [23], age [23] or the number of previous relapses [23]). In a subgroup of DMT-naive patients recently diagnosed with RMS (n = 587 pooled TEMSO and TOWER;
mean baseline EDSS score 2.0), teriflunomide treatment (14 mg/day) was associated with a significantly greater prob- ability of freedom from MRI-assessed disease activity than placebo (odds ratio 2.46; p = 0.0079), with a relative risk reduction in the ARR at 5 years of 32.7% (p = 0.0189) [24]. In TEMSO, MRI-assessed disease-activity outcomes also favoured teriflunomide over placebo during the 2-year study period, with a teriflunomide dose-dependent effect evident for several imaging metrics [7, 25, 26]. Compared with pla- cebo (n = 363), there were significantly smaller increases in the teriflunomide 14 mg group (n = 359) in total lesion volume (increase was 67.4% lower; p < 0.001), the volume of hypointense component lesions on T1-weighted images (increase was 31.3% lower; p < 0.05) and hyperintense lesion components of T2-weighted images (increase was 76.7% lower; p < 0.001) [7, 25]. The estimated number of Gd-enhancing lesions per T1-weighted scan was also sig- nificantly lower with teriflunomide 14 mg/day than placebo (relative risk 0.20; 95% CI 0.012–0.32; p < 0.001) [7, 25].
Teriflunomide significantly (p = 0.0001) reduced BVL from
baseline at 1 (median BVL 0.39 vs. 0.61% with placebo; relative reduction 36.9%) and 2 years (median BVL 0.90 vs. 1.29%; relative reduction 30.6%), which is suggestive of a neuroprotective effect and consistent with the effects of teriflunomide in delaying disability worsening [26]. BVL was analyzed by structural image evaluation using normali- zation of atrophy (SIENA), a well-established, longitudinal registration-based technique for detecting BVL over time [26]. In a pooled analysis of patients with RMS (phase 2 and TEMSO trials) or a first clinical demyelinating episode (TOPIC trial; Sect. 2.1.2), at 108 weeks’ follow-up, terif- lunomide 14 mg/day treatment reduced the adjusted num- ber of unique active lesions/scan by 61.4% (1.37 vs. 3.54 lesions/scan in the placebo group; p < 0.0001) [27]. Based on SIENA analyses, a strong correlation was shown between BVL over 2 years and confirmed disability worsening in teriflunomide recipients participating in the TEMSO core and extension study, with patients in the highest quartile for BVL having a greater probability of 3- and 6-month con- firmed disability worsening at 5 years than those in the low- est quartile for BVL [28].
⦁ Versus Interferon β‑1a In TENERE, adults with RRMS received teriflunomide (7 or 14 mg/day; results are for the 14 mg group; n = 109 and 111) or subcutane- ous IFNβ-1a (44 μg three times/week; recommended dos- age; n = 104) for ≥ 48 weeks [9]. The primary composite endpoint was the time to treatment failure, defined as first occurrence of confirmed relapse or permanent discontinua- tion for any cause.
There was no significant difference between the terifluno- mide and IFNβ-1a group for the time to treatment failure at weeks 48 and 96, based on Kaplan–Meier methods, [9] with

superiority criteria for teriflunomide versus IFNβ-1a not met for the primary composite endpoint [4]. Cumulative percent- ages of estimated failures in the teriflunomide and IFNβ-1a group were 33 and 37% at week 48, and 37.8 and 42.3% at week 96 [9]. At week 48, there was no between-group dif- ference in the ARR (0.26 vs. 0.22 relapses/PY’ exposure; relative risk 1.20; 95% CI 0.62–2.30) or mean change in total FIS score (+4.10 vs. +9.10). Mean Treatment Satisfaction Questionnaire for Medication (TSQM; score range 0–100; higher scores = greater satisfaction) scores significantly favoured teriflunomide treatment for the domains of side effects (mean score 93.15 vs. 71.38 in the IFNβ-1a group; p < 0.0001), convenience (89.85 vs. 61.90; p < 0.0001) and
global satisfaction (68.82 vs. 60.98; p < 0.05) at 48 weeks, with no significant difference for the mean change in the TSQM effectiveness domain score (63.13 vs. 59.30) [9].
⦁ In Patients with a First Clinical Demyelinating Episode

The efficacy of teriflunomide 7 or 14 mg once daily in adult patients (mean age 32 years) with a first clinical demyelinating episode was evaluated in the 108-week, ran- domized, double-blind, placebo-controlled, multinational, phase 3 TOPIC trial [29]. A first clinical demyelinating
episode was defined as a neurological event consistent with demyelination, starting within 90 days of randomiza- tion or ≥ 2 T2-weighted MRI lesions ≥ 3 mm in diameter. The primary outcome, analysed in the modified intent-to- treat population, was the time to relapse (i.e. a new neu- rological abnormality separated by ≥ 30 days from a pre- ceding clinical event, present for ≥ 24 h with the absence of fever or known infection), which defined conversion to clinically definite MS (CDMS). The median duration on study treatment in the teriflunomide 14 mg and placebo group was 633 and 504 days [29].
During the 2 year study period, relative to placebo, terif- lunomide reduced the risk of relapse defining CDMS by 43% (Table 3) [29]. Most secondary clinical and MRI-assessed endpoints also favoured teriflunomide over placebo, includ- ing the time to relapse or detection of new Gd-enhancing or T2-weighted lesions, mean change in EDSS score and mean change in total lesion volume (Table 3) [29]. Consist- ent with its beneficial effects in reducing the risk of con- version to CDMS, teriflunomide 14 mg/day slowed cortical grey matter atrophy [30] and whole brain atrophy [31] at all evaluated timepoints (month 6, 12, 18 and 24), with signifi- cant (p < 0.05 at all timepoints) reductions in MRI-assessed median percentage cortical grey matter volume loss [30] and whole BVL [31] with teriflunomide compared with placebo.

Table 3 Efficacy of oral teriflunomide in the phase 3 TOPIC trial in adults with a first clinical demyelinating episode

Endpoints Teriflunomide 14 mg/day Placebo
Clinical Endpointsa
HR for Time to relapse → CDMSb 0.574 (95% CI 0.379–0.869)** [RR 42.6%]
% pts with relapse 18 28
HR for time to relapse or MRI lesionc 0.651 (95% CI 0.515–0.822)*** [RR 34.9%]
% of pts with relapse or lesionc 64 76
ARR (no. of confirmed relapses/pt-year’ exposure) 0.194 [RR 31.9%] 0.284
3-month sustained disability worseningd (% of pts) 7 (0.701; 0.360–1.366) [RR 31.9%] 10
Mean change from BL in EDSS score [BL value] − 0.265* [BL 1.8] − 0.056 [BL 1.71]
MRI-assessed disease activity endpointse
Mean change total lesion volume (mL) − 0.028* [BL 8.78] +0.044 [BL 9.15]
Adjusted estimated no. Gd-enhancing T1 lesions/scan post BL 0.395*** [RR58.5%] 0.953
Volume of Gd-enhancing T1 lesions post BLf (mL) 0.034**** 0.079
Results from the double-blind, multinational TOPIC trial at week 108 week [29]. Included a TER 7 mg/day group; dosage is not approved in the EU (not tabulated). Adapted from Miller et al. [29], with permission
ARR adjusted annualized relapse rate, BL baseline value, CDMS clinically definite multiple sclerosis, EDSS Expanded Disability Status Scale,
Gd gadolinium, HR hazard ratio, pt(s) patient(s), RR risk reduction vs. PL, → indicative of conversion to CDMS
*p < 0.05, **p < 0.01, ***p < 0.001, **** p < 0.0001 vs. PL
aModified intent-to-treat population; n = 214 in the teriflunomide group and 197 in the placebo group
bPrimary endpoint
cKey secondary endpoint; relapse or detection of new Gd-enhancing or T2-weighted lesion on MRI scan
dIncrease from baseline of ≥ 1.0 in EDSS score (or ≥ 0.5 in pts with a baseline EDSS score of > 5.5) that persisted for ≥ 12 weeks
eEvaluable pts; n = 199 in the teriflunomide group and 177 in the placebo group
fTotal volume of Gd-enhancing lesions that occurred during the study divided by no. of scans

The beneficial effects of teriflunomide in this patient population were maintained during ≤ 7 years’ treatment in the extension phase of TOPIC (n = 423 entered the exten- sion phase and 316 completed it) and consistent with those observed in long-term extension studies in patients with a broad spectrum of RMS subtypes (Sect. 2.1.1) [32]. During the extension, patients continued to receive the teriflunomide dosage they were randomized to in the core study, with pla- cebo recipients re-randomized to teriflunomide 7 or 14 mg/ day. During 7 years’ follow-up, there was a 47% reduction in the risk of relapse determining conversion to CDMS [hazard ratio (HR) 0.529; 95% CI 0.317–0.883; p < 0.02 vs.
placebo], the ARR was ≤ 0.163 relapses/PY’ exposure and the majority of patients remained relapse free (≥ 61% across all treatment groups) or free of 3-month sustained disability worsening (≥ 78%) [32].
⦁ In Postmarketing and Real‑World Studies
⦁ Clinical and MRI‑Assessed Outcomes

The efficacy of teriflunomide in the real-world setting in patients with RMS was established in large (n > 900), pro- spective [phase IV, multinational, single-arm study (Teri- PRO) [33–35] ] and multicentre, observational studies [36–42] ] and US retrospective database studies [43–45], some of which also evaluated other outcomes such as treat- ment satisfaction and discontinuation rates (Sect. 2.2.2). Given the inherent limitations of retrospective studies, dis- cussion in this section focuses on results from prospective studies.
In the Teri-PRO study (n = 1000) in which patients received teriflunomide 7 mg/day (only US participants) or 14 mg/day (92.8% received the 14 mg dose) for 48 weeks, 59% of patients had switched to teriflunomide from another DMT (from IFNβ 50.7% of patients, glatiramer acetate 24.4%, dimethyl fumarate 12.5%, natalizumab 7.6% or fin- golimod 4.9%) within the previous 6 months (18% of whom switched because of disease worsening); 80.6% of patients completed the study [33]. Clinician-assessed (i.e. EDSS scores and ARR) and patient-reported [Patient-Determined Disease Steps (PDDS) scale and MS Performance Scale (MSPS) assessments] disability outcomes remained stable during 48 weeks’ treatment (secondary outcomes), includ- ing cognitive outcomes (assessed by Symbol Digit Modali- ties Test), irrespective of whether patients had or had not received prior DMT. In patients switching from prior DMT, the ARR was low during the entire study period (0.18–0.30 relapses/PY’ exposure), with minimal changes from baseline in mean EDSS (3.1 at baseline vs. 3.0 at week 48), PDDS (2.2 vs. 2.2) and MSPS (12.3 vs. 11.9) scores. Quality of life (QOL) also remained stable over the study period, as assessed using the Stern Leisure Activity Scale and MS
International QOL (MusiQOL) scale, in the overall popula- tion and those who switched to teriflunomide from previous DMT [33]. In post hoc analyses, improvements in disabil- ity outcomes were comparable between the US population (n = 545) and rest of the world (ROW; n = 455) populations, irrespective of differences in baseline demographics and treatment management between these geographical regions [35].
In general in nonrandomized, observational studies eval- uating first-line treatment with teriflunomide or dimethyl fumarate in RRMS, ARRs were higher in teriflunomide than dimethyl fumarate recipients, with results for other efficacy measures equivocal [36, 37, 39, 40]. Based on data from the German NeuroTransData registry (n = 388 in each propensity matched cohort for teriflunomide and dimethyl fumarate), the time to first relapse was significantly shorter in teriflu- nomide than dimethyl fumarate recipients (primary outcome; by non-pairwise censoring), as assessed using Kaplan–Meier estimates (HR 0.531; 95% CI 0.377–0.747; p = 0.0003) [37].
The ARR was also significantly higher in teriflunomide than dimethyl fumarate recipients (0.215 vs. 0.117 relapses/PY’ exposure; HR 0.546; 95% CI 0.387–0.771; p = 0.001). There
was no significant between-group difference for the time to 3- and 6-month confirmed EDSS disability worsening events or the proportion of progression-free patients at 12 months in exploratory analyses [37]. In a global longitudinal cohort study (n = 2985), teriflunomide treatment was associated with a higher ARR than dimethyl fumarate (0.26 vs. 0.17 relapses/ PY’ exposure) or fingolimod (0.24 vs. 0.18 relapses/PY’ expo- sure) over a 2-year follow-up period, with no between-group differences in disability worsening or improvements [36]. In a Danish study, at a mean follow-up of 2 years, ARRs in the teriflunomide and dimethyl fumarate group were 0.19 and
0.11 relapses/PY’ exposure (adjusted rate ratio teriflunomide/ dimethyl fumarate 1.3; 95% CI 1.14–1.49), with the time to first relapse (HR 0.55; 95% CI 0.43–0.71) also favouring dime- thyl fumarate over teriflunomide treatment [40]. There was no significant between-group difference for the time to 6-month confirmed EDSS worsening [40]. In a French study (n = 1770) [39], after correction for confounders, the risk of relapse (≈ 21 and 30% had experienced ≥ 1 relapse at 1 and 2 years in both groups) and worsening of EDSS scores (≈ 27 and 41%) were similar at 1 and 2 years in the teriflunomide and dimethyl fumarate groups. However, teriflunomide treatment was asso- ciated with a higher confounder-adjusted proportion of patients with ≥ 1 new T2-weighted lesion at 2 years than dimethyl fumarate (72.2 vs. 60.8%; odds ratio 0.6; 95% CI 0.41–0.74) [39]. In the retrospective Teri-RADAR study (n = 100), the mean annualized percentage whole brain change favoured teriflunomide over dimethyl fumarate treatment (mean change from pre-index period (− 0.1 vs. − 0.5; p = 0.0212), with no between-group differences for other MRI metrics such as the

percentage of patients with new/enlarging T2 or Gd-enhancing lesions (30 vs. 40%) [46].
⦁ Other Patient‑Reported and Tolerability Outcomes

Several large (n > 900), prospective [33–37, 40, 47] and retro- spective [48–50] studies have evaluated treatment satisfaction [33, 34, 47], discontinuation [36, 37, 40, 48–50], persistence
[49] and/or adherence/compliance [48, 49] rates amongst patients with RRMS receiving oral DMTs in the real-world setting.
In Teri-PRO, teriflunomide treatment was associated with high scores in all TSQM domain scores at 48 weeks, includ- ing for the global satisfaction domain in the overall popula- tion (primary endpoint) and in patients who switched from a prior DMT [33–35]. TSQM was assessed at 4 and 48 weeks in patients with no prior DMT use within 6 months of baseline, and at 4 and 48 weeks in those who switched from a prior DMT to teriflunomide. In the overall population, mean scores were high at week 4 and 48 for the TSQM domains of Global Satisfaction (72.3 and 68.2), effectiveness (67.1 and 66.3), side
effects (88.4 and 84.1) and convenience (92.3 and 90.4) [34]. In patients who had switched to teriflunomide from a prior DMT, there were significant (all p < 0.001) improvements from baseline at week 4 and 48 for all TSQM domains, with the effect size for the global satisfaction (0.78), side effects (0.69) and convenience (1.31) domains considered moderate to high and a smaller effect size seen for the effectiveness domain (0.47) [34]. Improvements in treatment satisfaction were com- parable regardless of geographic region (USA and ROW), based on post hoc analyses [35]. These data are supported by results from the German TAURUS-MS 1 observational study, in which TSQM global satisfaction domain scores increased from week 1 through to week 96 in patients switching to teri- flunomide from another DMT [47].
In observational studies, treatment discontinuation rates and the time to treatment discontinuation were generally similar in teriflunomide and dimethyl fumarate recipients [36, 37], with discontinuation rates higher (both p < 0.001 vs. fingolimod) [36] and the time to treatment discontinua- tion shorter (no p values reported) [37] in these two groups than in oral fingolimod recipients. Conversely, in the larg- est retrospective claims analysis (n > 26,000 in the overall cohort), discontinuation (25–31 vs. 24–29%) and compli- ance (68–77 vs. 70–75%) rates were similar in teriflunomide and fingolimod recipients at 6, 12 and 24 months [48].

⦁ Tolerability of Teriflunomide
Teriflunomide was generally well tolerated in the clinical trial and real-world settings in adults with RMS involved in studies discussed in Sect. 2. Discussion focuses on a pooled
analysis of four placebo-controlled trials (safety population) in patients with RMS receiving teriflunomide 7 or 14 mg/day (n = 2047; cumulative exposure of > 1500 PYs’ exposure/ group) or placebo (n = 997) [4, 51]. Results in the pooled analysis were consistent with data from each individual trial and a similar tolerability profile was observed with both dos- ages of teriflunomide [51].
The most commonly reported treatment-emergent adverse events (TEAEs) in the teriflunomide 14 mg and pla- cebo groups were headache (15.7 and 15.0% of patients), increased alanine aminotransferase (ALT; 15.0 and 8.9%), diarrhoea (13.6 and 7.5%), alopecia (13.5 and 5.0%) and
nausea (10.7 and 7.2%) [51]. Although the majority of patients in these respective groups experienced ≥ 1 TEAE (88 and 86%), most were of mild to moderate severity, transient and infrequently led to treatment discontinuation. An increase in ALT level was the most common reason for discontinuing treatment with teriflunomide 14 mg/day or placebo (2.6 and 2.3% of patients), mostly reflecting trial protocols which required treatment discontinuation on con- firmation of an ALT increase of > 3 × upper limit of normal (ULN). Serious adverse events (SAEs) occurred in 13.3 and 11.9% of patients in the teriflunomide 14 mg and placebo groups, with increased ALT levels the only such event to occur in > 1% of patients in either group (1.3 and 1.6%). No new safety concerns were identified during the extension phases of these trials (n = 2338; ≤ 12 years’ teriflunomide treatment; > 6800 PYs’ exposure/group) [51].
In TENERE, teriflunomide appeared to be as well tol- erated as IFNβ-1a, with no unexpected safety findings for either agent [9]. Common TEAEs (incidence ≥ 10% in any group) reported numerically more frequently with terifluno- mide 14 mg than IFNβ-1a were nasopharyngitis (20.0 and 17.8%), diarrhoea (20.9 and 7.9%), hair thinning (20.0 and
1.0%), paresthesia (10.0 and 7.9%) and back pain (10.0 and 6.9%). Conversely, those occurring with a lower frequency in the teriflunomide than IFNβ-1a group were influenza-like symptoms (2.7 and 53.5%), increased ALT levels (10.0 and
30.7%) and headache (15.5 and 25.7%). Increased ALT level was the only SAE to occur in > 1% of patients in either treat- ment group (0.9% of teriflunomide and 1.0% of IFNβ-1a recipients), with all cases being asymptomatic and revers- ible [9].
3.1 Adverse Events of Special Interest

In the safety population, hepatic events involving increased ALT levels of > 3 × ULN occurred in 8 and 6.6% of teri- flunomide 14 mg/day and placebo recipients and levels of > 5 × ULN occurred in 3.1 and 3.7%, most of which occurred in the first 6 months of treatment and resolved upon discontinuation of treatment [4]. Although two teri- flunomide 14 mg/day and five placebo recipients had ALT

levels > 3 × ULN concurrently with total bilirubin lev- els > 2 × ULN, there was no suggestion of drug-induced liver injury and an alternative explanation beyond study treatment was identified in each case [51]. Monitoring ALT and other liver enzymes is recommended before initiating terifluno- mide and during treatment [4].
There was no increase in the frequency of any infections (52.7 and 53.4%) or serious infections (2.7 vs. 2.2%) in the teriflunomide 14 mg group relative to the placebo group, with serious opportunistic infections occurring in 0.2% of patients in each group [51]. Given that teriflunomide is an immunomodulator, treatment should be delayed in patients with severe active infection until resolution and, if a patient develops a serious infection during teriflunomide treatment, suspending treatment should be considered and the benefits and risks should be reassessed prior to re-initiating teriflu- nomide [4]. The safety of teriflunomide in individuals with latent tuberculosis is unknown, as tuberculosis screening was not systematically performed in clinical studies; for patients testing positive in tuberculosis screening, treat by standard practice prior to teriflunomide therapy [4].
In placebo-controlled trials, teriflunomide treatment was associated with reductions in white blood cell (WBC) counts (mean decrease < 15% from baseline level, mainly neutrophils and lymphocytes) [51], with complete blood count monitoring recommended before and during treatment [4]. In general, reductions in neutrophils and lymphocytes occurred during the first 6 weeks or 3 months, respectively, with counts remaining stable thereafter [51]. In the teriflu- nomide 14 mg and placebo groups, neutropenia occurred in
5.9 and 1.9% of patients and lymphopenia in 0.5 and 0.2%, with no cases of febrile neutropenia reported. One patient experienced serious thrombocytopenia, which was consid- ered to be possibly related to teriflunomide therapy (based on its mechanism of action). No correlation between reduced neutrophil counts and the occurrence of infections was observed. [51]. In the real-world Teri-PRO study, changes in lymphocyte counts were consistent with those observed in other clinical trials [52]. Results from the TOWER core and extension studies [53] and a pooled analysis of the TEMSO and TOWER core and extension studies [54] also demon- strated a lack of association between infection rates and reduced lymphocyte counts, with rates of infection similar irrespective of the presence or absence of lymphopenia.
Monitoring of BP is recommended before starting teriflu- nomide treatment and periodically during treatment [4]. In the teriflunomide 14 mg and placebo groups in placebo-con- trolled studies, systolic BP (SBP) > 140 mg Hg occurred in 19 and 15% of patients, SBP > 160 mmHg in 3.8 and 2.0%,
and diastolic BP > 90 mm Hg in 21.4 and 13.6% [4].
Although immunosuppressant drugs are associated with an increased risk of malignancy (especially lymphoprolif- erative disorders), there is no apparent increase in the risk
of malignancy with teriflunomide treatment based on the clinical experience, including in extension studies [4, 51]. In placebo-controlled trials, one case of cervical carcinoma (stage 0) occurred in the teriflunomide 14 mg group, with two cases of breast cancer and one case each of thyroid can- cer and cervical carcinoma (stage 0) reported in the pla- cebo group [51]. No lymphoproliferative or haematological malignancies were reported during long-term teriflunomide treatment in extension studies. These results are consistent with the lack of a measurable increase in the risk of malig- nancy during long-term treatment with leflunomide (in vivo precursor) [51].
Teriflunomide is contraindicated in pregnancy (and dur- ing breast feeding), and in female patients of reproductive potential not using an effective contraceptive, as it may be associated with serious birth defects based on the teratogenic and embryolethal effects observed in preclinical studies [4]. If required, plasma levels of teriflunomide may be rapidly reduced by instituting the accelerated elimination procedure (involves absorption therapy using cholestyramine or acti- vated charcoal treatment; see local prescribing information for full details). Based on clinical trial and 5-year postmar- keting data (cut-off December 2017), the evidence from 222 confirmed teriflunomide pregnancies with known outcomes (n = 70 from clinical trials and 152 from postmarketing data) was consistent with that observed in the general population [55]. Of these 161 and 61 prospectively and retrospectively reported pregnancies with known outcomes, there were 107 live births, 63 elective abortions, 47 spontaneous abortions, 3 ectopic pregnancies, 1 stillbirth and 1 maternal death lead- ing to fetal death. A case of uteropyeloectasia was the only birth defect of four that was considered to be major; other defects were congenital hydrocephalus, ventricular septal defect and malformation of the right foot valgus. A struc- tural abnormality (cystic hygroma) was detected on an ultra- sound scan in a woman for whom the pregnancy outcome is unknown [55]. These data are supported by evidence from earlier retrospective analyses of clinical and/or postmarket- ing data [56, 57], and Danish [58] and French [59] registry- based studies.
Cases of peripheral neuropathy have been reported
in patients treated with teriflunomide, with most patients improving after discontinuation of treatment [4]. Peripheral neuropathy, including polyneuropathy and mononeuropathy, was reported more frequently in teriflunomide than placebo recipients in pivotal placebo-controlled trials (1.9% of 898 patients vs. 0.4% of 898 placebo-treated patients). Five patients receiving teriflunomide 14 mg/day who developed peripheral neuropathy discontinued treatment, with four of these patients recovering following treatment discontinua- tion [4].
In the postmarketing setting, cases of severe skin reac- tions (e.g. Stevens-Johnson syndrome and toxic epidermal

necrolysis) and interstitial lung disease (ILD) have been reported with teriflunomide treatment, with worsening of pre-existing ILD reported during leflunomide treatment [4]. Two clinical studies have shown that vaccinations to inactivated neoantigen (first vaccination) or recall antigen (re-exposure) were safe and effective during teriflunomide treatment [4]. The use of live attenuated vaccines may carry
a risk of infections and should therefore be avoided [4].

⦁ Dosage and Administration of Teriflunomide
Oral teriflunomide is approved in numerous countries, including in the EU [4] and the USA [10], for treating RMS; the specific indication may vary in individual coun- tries. In the EU, teriflunomide is approved for the treat- ment of adult patients with RRMS; the recommended dos- age is 14 mg once daily [4]. A lower dosage of 7 mg once daily is also available in the USA [10], but not in the EU or elsewhere. Under certain circumstances (e.g. pregnancy, emerging SAEs), accelerated elimination of teriflunomide with cholestyramine or activated charcoal powder is rec- ommended [4, 10]. Local prescribing information should be consulted for further details, including contraindications, precautions, warnings, drug interactions, use in special patient populations and accelerated elimination instructions.

⦁ Place of Teriflunomide in the Management of RRMS
The heterogeneous and complex nature of MS requires a multifaceted, individualized approach to its management, mainly consisting of symptomatic treatment and DMT to prevent relapses and disease progression, with the ultimate long-term goal to reduce the burden of disease disability [60, 61]. Current joint guidelines of the European Com- mittee of Treatment and Research in MS (ECTRIMS) and the European Academy of Neurology (EAN) recommend several DMTs (modest to high efficacy) for active RRMS, including subcutaneous IFNβs (IFNβ-1a, IFNβ-1b, peginter- feron β-1a), subcutaneous glatiramer acetate, intramuscular IFNβ-1a, oral agents (fingolimod, dimethyl fumarate, teriflu- nomide), intravenous monoclonal antibodies (alemtuzumab, natalizumab, ocrelizumab) and intravenous mitoxantrone [60]. DMTs should be initiated as early as possible in RMS (as defined by clinical relapses and/or MRI activity), includ- ing in patients with clinically isolated syndrome fulfilling current diagnostic criteria for MS (only IFNβs and glati- ramer acetate are recommended) [60]. The ECTRIMS/EAN
[60] and UK NICE [62] guidelines recommend terifluno-
mide as an option for treating active RRMS (in the UK, only
if they do not have highly active or rapidly evolving severe RRMS and if the manufacturer provides the drug with the discount agreed in the patient access scheme [62]). Recom- mendations in the recent American Academy of Neurology (AAN) guidelines [61, 63] are generally similar to those of ECTRIMS/EAN [60].
The availability of several new DMTs in the last decade, especially for RRMS, represents a significant advance in the treatment algorithm for MS, but has also added to the complexity of decision making in its management [60, 61]. Choosing between this broad spectrum of DMTs depends on multiple factors, including patient characteristics and comor- bidities, disease activity and severity, drug safety profiles, accessibility of the drug, and preferences of patients and neurologists. This decision is exacerbated by the absence of comparative head-to-head randomized controlled trials (RCTs) for oral DMTs to definitively establish the relative efficacy of these drugs and the lack of a biomarker to facili- tate identifying the best choice for each patient [60, 61].
Alongside considering the convenience of administration (e.g. route, frequency of doses), the benefit-risk profile of each DMT is a key consideration, with drugs ranging from more effective but potentially harmful to less effective but safer [1, 60]. Safety concerns with various DMTs include a risk of progressive multifocal leukoencephalopathy (PML) with natalizumab and fingolimod (rare PML cases have also been reported with dimethyl fumarate), cardiotoxicity with fingolimod and mitoxantrone, the risk of lymphopenia with dimethyl fumarate, and myelosuppression with mitox- antrone, with all DMTs associated with a risk of infection [1, 2]. A rare case of PML was reported in a patient with MS receiving teriflunomide after discontinuing natalizumab treatment ≈ 5.5 months earlier [64]. After ≈ 3 months of teri- flunomide, the patient developed right-side weakness and anomic aphasia, with radiologic features suggestive of PML. Teriflunomide treatment was discontinued immediately and the patient underwent accelerated elimination of the drug using cholestyramine. Evidence suggests this case may have been related to previous natalizumab treatment, with other PML cases occurring up to 6 months after discontinu- ing natalizumab [64]. It is unknown whether this case was related to teriflunomide treatment.
With the exception of glatiramer acetate, current DMTs
are not licensed for use during pregnancy [60], with ECTRI- MIS/EAN and AAN guidelines advising against the use of DMTs during pregnancy [60, 61, 63]. ECTRIMS/EAN guidelines advise continuing IFNβ or glatiramer acetate therapy until pregnancy is confirmed for women who are planning a pregnancy and also to consider continuing the treatment during pregnancy if the woman is at risk of MS reactivation [60]. Women with high disease activity are advised to delay pregnancy and, if despite this advice, women still decide to become pregnant or have an unplanned

pregnancy, treatment with natalizumab or alternatively alemtuzumab should be considered after full discussion of the potential implications [60].
Extensive experience in the clinical trial (Sect. 2.1) and real-world settings (Sect. 2.2) has established the efficacy of oral teriflunomide in reducing relapse rates and disease activity in adults with RMS, with these beneficial effects maintained during ≥ 10 years’ follow-up (Sect. 2.1.1). In pivotal RCTs, teriflunomide provided significantly bet- ter efficacy than placebo (TEMSO and TOWER) and was as effective as IFNβ-1a (TENERE) in patients with RMS (Sect. 2.1.1). The beneficial effects of teriflunomide over placebo occurred across all pre-specified subgroups of patients, including based on baseline demographics, dis- ease characteristics, MRI-assessed disease activity and prior use of other DMTs (Sect. 2.1.1). Albeit the efficacy of teriflunomide 14 mg/day did not differ from that of IFNβ-1a in the primary analysis in TENERE, patient-rated TSQM scores favoured teriflunomide treatment for three of the four subdomains (i.e. for side effects, convenience and global satisfaction; Sect. 2.1.1). High treatment satisfaction scores with teriflunomide were also observed in the real-world Teri-PRO phase IV and TAURUS-MS 1 studies, including for TSQM global satisfaction domain scores and irrespec- tive of whether patients had or had not received prior DMT (Sect. 2.2.2). In patients with a first demyelinating episode, teriflunomide reduced the risk of a relapse defining CDMS by 43% compared with placebo during the 2-year TOPIC trial, with other clinical and MRI-assessed outcomes also favouring teriflunomide (Sect. 2.1.2). In the absence of head- to-head trials, the relative efficacy of oral DMTs remain to be definitively established; typically in observational studies evaluating first-line treatment with teriflunomide or dimethyl fumarate in RRMS, ARRs were higher with teriflunomide than dimethyl fumarate treatment, with results for other effi- cacy measures equivocal (Sect. 2.2.1).
Teriflunomide was generally well tolerated in the clini-
cal trial and real-world settings, with most TEAEs of mild to moderate severity, transient, and infrequently leading to treatment discontinuation (Sect. 3). The most common TEAEs occurring during teriflunomide treatment were head- ache, increased ALT levels, diarrhoea, alopecia and nau- sea. Teriflunomide was as well tolerated as IFNβ-1a, with adverse events occurring with each of these drugs consistent with their known tolerability profiles. The tolerability profile of teriflunomide during long-term treatment was consistent with that observed during shorter-term treatment, with no new safety signals identified during ≥ 10 years’ treatment. Given the known tolerability and safety profile of teriflu- nomide, regular monitoring of ALT levels and complete blood cell counts are required during treatment, as is peri- odical monitoring of BP (Sect. 3.1). The drug is contrain- dicated in pregnancy, with preclinical studies suggesting
that teriflunomide may be associated with teratogenic and embryolethal effects (Sect. 3.1). However, to date, consistent with 20-year postmarketing data for leflunomide, no tera- togenic signal has been observed in teriflunomide-exposed pregnancies and no pregnancy safety concerns have been identified (Sect. 3.1). Albeit teriflunomide has a prolonged half-life (Table 1), the drug can be rapidly eliminated under certain circumstances (e.g. pregnancy, emerging SAEs) using absorption therapy [4, 10].
In conclusion, based on extensive evidence from RCTs and the real-world setting, teriflunomide is an effective and generally well tolerated treatment in patients with RMS, with benefits maintained during long-term treatment and no new safety signals identified. In pivotal RCTs, teriflunomide provided significantly better efficacy than placebo and was as effective as IFNβ-1a in terms of improvements in clinical outcomes and/or MRI-assessed disease activity measures. Albeit head-to-head trials would definitively establish the relative efficacy of oral DMTs, given its convenient oral regi- men and beneficial effects in reducing relapses and disease activity, teriflunomide remains an effective option for the management of RRMS.

Data Selection Teriflunomide: 790 records identified
Duplicates removed 114
Excluded during initial screening (e.g. press releases; news reports; not relevant drug/indication; preclinical study; reviews; case reports; not randomized trial) 418
Excluded during writing (e.g. reviews; duplicate data; small patient number; nonrandomized/phase I/II trials) 194
Cited efficacy/tolerability articles 52
Cited articles not efficacy/tolerability 12
Search Strategy: EMBASE, MEDLINE and PubMed from 2013 to present. Previous Adis Drug Evaluation published in 2013was hand-searched for relevant data. Clinical trial registries/databases and websites were also searched for relevant data. Key words were teriflunomide, Aubagio, a-771726, rs061980, su-0020,
hmr-1726*. Records were limited to those in English language. Searches last updated 2 May 2019.

Acknowledgements During the peer review process, the manufacturer of teriflunomide was also offered an opportunity to review this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.
Compliance with Ethical Standards
Funding The preparation of this review was not supported by any external funding.

Conflicts of interest Lesley Scott is a salaried employee of Adis Inter- national Ltd./Springer Nature, is responsible for the article content and declares no relevant conflicts of interest.

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