Pathophysiology of multiple sclerosis and the place of teriflunomide


J. S. Wolinksy, Department of Neurology, The University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USA
Tel.: +1 713 500 7048
Fax: +1 713 500 7041


Gold R, Wolinsky JS. Pathophysiology of multiple sclerosis and the place of teriflunomide.
Acta Neurol Scand: 2011: 124: 75–84.
© 2010 John Wiley & Sons A/S.

Significant progress in multiple sclerosis (MS) treatment has been made over the last two decades, including the emergence of disease-modifying therapy (DMT). However, substantial unmet medical need persists and has stimulated the search for new therapeutics. Teriflunomide, one of the several oral DMTs under investigation, is a selective inhibitor of de novo pyrimidine synthesis which exerts a cytostatic effect on proliferating T- and B lymphocytes in the periphery and thus has both antiproliferative and anti-inflammatory properties. Anti-inflammatory effects have been demonstrated in rodent MS models, with reductions in macrophage and B- and T-cell infiltration in the central nervous system and preservation of myelin and oligodendrocytes. Delays in disease onset, reductions in disease relapses and improvements in clinical symptoms were also observed. A proof-of-concept clinical trial in patients with relapsing MS demonstrated that teriflunomide significantly reduced magnetic resonance imaging (MRI) activity and improved clinical endpoints, with both effects maintained with longer-term treatment. Additional studies have shown that teriflunomide can be safely added to beta interferon or glatiramer acetate therapy, with some evidence of additional improvements in MRI disease burden and clinical signs. Teriflunomide has an acceptable and manageable safety and tolerability profile. A large clinical programme is underway to further elucidate the role of teriflunomide in the treatment of MS.


Multiple sclerosis (MS) is a chronic, progressive, degenerative neurological disease, associated with immune system deregulation, culminating in demyelination and axonal damage within the central nervous system (CNS) (1). MS is one of the most common neurological diseases in young adults and the leading cause of non-traumatic disability in young and middle-aged adults (2). About 2 million people are living with MS worldwide, with the number of cases expected to increase as population growth continues (3, 4).

MS disease subtypes

Most patients with MS (∼85%) experience a relapsing/remitting (RRMS) disease course followed by progressive decline in function [secondary progressive MS (SPMS)] (5, 6). A small proportion of patients (∼10%) do not experience relapses and instead have a progressive course from the outset [primary progressive MS (PPMS)] (7). About 10–15% of patients with RRMS have a mild disease course and can remain clinically stable for several decades (benign MS). The onset of MS in the majority of cases is preceded by a first presentation of demyelinating disease termed a clinically isolated syndrome (CIS), involving either focal or multifocal regions of the CNS, most frequently in the optic nerve, brainstem or spinal cord (8). MS in general is 2–3 times more prevalent in females than in males, although no gender imbalance is seen in PPMS (7). MS predominates among Caucasians and those of northern European descent (9).


MS is thought to arise from a breakdown in immune system regulation resulting from genetic predisposition and/or environmental factors, possibly including viral infections (10–12). In support of an environmental aetiology is the latitude gradient in MS distribution, with MS prevalence increasing with increasing distance from the equator (13). Furthermore, individuals growing up in high-prevalence areas remain at a high risk of MS after moving to low-risk regions, although this risk declines the longer they reside in these areas. Conversely, migration to high-risk areas in childhood increases the risk of MS (14). Similar trends have been observed over generations with migration from one area to another. Such observations have led to the hypothesis that low vitamin D levels from reduced sun exposure in Northern latitudes may predispose individuals to MS (15). A protective effect of vitamin D is further supported by the observation that high circulating levels of vitamin D are associated with a lower risk of MS (15).

Although not inherited in a Mendelian fashion, there is a strong genetic contribution to the aetiology of MS (13). First-degree relatives have a 1–5 times increased risk of MS, while the concordance rate in monozygotic twins is about 35% (16–18). Patients carrying the class 2 major histocompatability complex (MHC) HLA-DR2 genes are particularly susceptible to MS (19, 20). Several risk loci beyond the MHC have also been identified, including the interleukin-7 (IL-7) receptor, the interleukin-2 receptor alpha chain (IL2RA) and CD58 (21).


MS plaques are focal areas of demyelination dispersed throughout the white matter of the brain and spinal cord, but also in the cerebral cortex and deep grey matter. Demyelination and inflammation can also be seen in normal-appearing white matter. Furthermore, substantial axonal injury, including axonal transection, occurs in active MS lesions (22). The inflammatory profile of MS lesions is characterized by perivascular infiltration of T cells, monocytes and occasional B cells and plasma cells (11). Three distinct acute MS lesion types have been proposed: type 1 lesions are dominated by T cells and macrophages; type 2 lesions have additional deposition of immunoglobulins and activated complement components; and type 3 lesions show evidence of oligodendroglial cell apoptosis (23). Lesions have a tendency to be of the same type within a single patient but can vary between patients and thus may reflect different stages of disease progression rather than distinct disease subtypes per se (11, 23).


MS is an immune-mediated disease involving both the cellular and humoral arms of the immune system. Current understanding of MS immunopathogenesis is derived from the experimental autoimmune encephalomyelitis (EAE) animal model, in which peripheral immunization with myelin components induces inflammatory demyelination within the CNS, a process mediated by myelin-specific T cells. This model has established that peripheral activation of autoreactive T cells leads to inflammatory disease in the CNS (24–26). Genetic manipulation studies in mouse MS models may also help to dissect other molecular mechanisms involved. However, rodent MS models are not without limitations, being heterogeneous in nature and influenced by the selected autoantigen, species and genetic background (24).

The generally accepted view of human MS immunopathogenesis implicates non-anergic myelin-specific autoreactive T cells activated in the peripheral immune system via an interplay between environmental triggers and genetic susceptibility (9). The precise mechanisms by which autoreactive T cells are activated remain unknown but may occur through non-specific polyclonal activation by bacterial or viral antigens or from structural homologies between a self-protein and a pathogenic protein (i.e. molecular mimicry). Although most MS models have focused on CD4 T cells, histopathological studies have more recently highlighted a role for inflammatory CD8 T cells (27).

After activation, T cells acquire the potential to cross the blood–brain barrier (BBB) (28). This process is driven by the expression of cell surface integrins (e.g. VLA-4) on inflammatory cells that mediate their binding to the vascular cell adhesion molecule (VCAM-1) expressed on capillary endothelial cells. VCAM-1 expression is induced by tumour necrosis factor (TNF)-α and interferon (IFN)-γ during inflammation. Matrix metalloproteases (MMPs) are released by T cells to facilitate their passage through the extracellular matrix. MMPs are also involved in the subsequent degradation of myelin components.

After entry into the CNS, T cells are reactivated on encountering CNS-related autoantigenic peptides in the context of class 2 molecules of the MHC expressed by local antigen-presenting cells and dendritic cells. This commits T cells towards a proinflammatory phenotype. Although Th1 cells were previously believed to be key players in MS immunopathogenesis, experimental MS models show an important role for a novel subset of inflammatory T cells, Th17 cells (29). Activated T cells cause myelin disruption, leading to the release of new CNS antigens. A cascade of proinflammatory cytokines and recruitment of additional inflammatory cells and specific myelin antibody-forming B cells to the site of inflammation further contributes to tissue injury (9, 12). The different stages in MS immunopathogenesis are summarized in Fig. 1.

Figure 1.

 The immunopathogenesis of multiple sclerosis. Autoreactive T-cells in the periphery are activated by an, as yet, unidentified mechanism, possibly involving molecular mimicry or bystander activation. Activation of these T cells gives them the potential to migrate across the blood–brain barrier (BBB) via an interaction of integrins on the T-cell surface with adhesion molecules on the endothelium of the BBB, followed by the degradation of the BBB via the secretion of matrix metalloproteases. Once in the central nervous system (CNS), T cells are reactivated on encountering local CNS antigens via an interaction with antigen-presenting cells such as macrophages or microglia, or B cells. T cells secrete proinflammatory cytokines, and plasma cells secrete antibodies against myelin, leading to the destruction of the myelin sheath. Ongoing inflammation in the CNS promotes the recruitment of additional inflammatory cells. Activated microglia release free radicals, nitric oxide and proteases, which further contribute to tissue damage and axonal loss.

MS treatment

MS treatment focuses on managing disease relapses and symptoms, with the aim of long-term prevention of, or at least reduction in, tissue damage. The broad spectrum of MS symptoms (i.e. sensory/motor defects, coordination abnormalities, visual disturbances, bladder/bowel dysfunction, sexual dysfunction, cognitive defects, fatigue) requires a multidisciplinary approach to treatment (30). The heterogeneity of MS also requires treatment decisions to be individualized for each patient; in reality, however, this remains a goal for the future.

Disease-modifying therapies (DMTs) have been available since 1990. For many years, two groups of drugs – the beta interferons (IFN-β) and glatiramer acetate (GA) – have been first line for RRMS (31). These agents impede the activation, proliferation and migration of inflammatory cells across the BBB; GA may also have a neuroprotective effect (32). Although these drugs reduce the frequency and severity of disease exacerbations and impact on lesion load as shown by magnetic resonance imaging (MRI), they are not without limitations (33). Indeed, they fail to prevent tissue damage accumulation and clinical disability in patients with longstanding, progressive phase disease. Furthermore, they are all administered parenterally, which limits long-term adherence and may impact on the opportunity for early intervention to prevent long-term damage. There is also an absence of effective treatments that address the progressive phase of MS. Consequently, significant unmet medical need persists in MS treatment (33). However, several agents are in development which seek to address the limitations of current DMTs through new modes of administration and with improved efficacy and safety. These agents differ in their mechanisms of action, which may influence their respective efficacy and safety profiles.

Teriflunomide is a novel immunomodulator targeting the immunoinflammatory basis of MS and holds significant promise for the future treatment of the disease. The remainder of this review focuses on the pharmacological, clinical and safety profile of teriflunomide and offers some insight into its future role in MS treatment.

Teriflunomide: drug profile

Mechanism of action

Teriflunomide possesses both antiproliferative and anti-inflammatory activities. These activities depend on potent (IC50 = 1.3 μm), non-competitive, selective and reversible inhibition of the mitochondrial enzyme, dihydroorotate dehydrogenase (DHODH) (34, 35). The net result is blockade of de novo pyrimidine synthesis and a subsequent cytostatic effect on proliferating T- and B-lymphocytes in the periphery, with no apparent cytotoxicity (Fig. 2) (36, 37). Cells that rely on DHODH-independent salvage pathways for pyrimidine synthesis (e.g. cells of the hematopoietic system and the gastrointestinal lining) are largely unaffected by teriflunomide’s antiproliferative effects, and thus the potential for significant cytopenia is reduced (38). The reduced availability of pyrimidines may also impact phospholipid synthesis and protein glycosylation in immune cells, thereby impairing the generation of lipid messengers and the function of cell surface molecules (Fig. 2). Thus, teriflunomide has the potential to impede T-cell activation in a multifaceted manner.

Figure 2.

 The mechanism of action of teriflunomide in the immune system. Teriflunomide blocks the de novo pathway of pyrimidine synthesis via a non-competitive and reversible inhibition of the mitochondrial enzyme, dihydroorotate dehydrogenase, and inhibits the proliferation of active T- and B-lymphocytes and suppresses antibody production in the periphery. Additional mechanisms have also been proposed.

Preclinical pharmacology

Teriflunomide has prophylactic (i.e. administered after induction of EAE) and therapeutic effects in the Dark Agouti (DA) rat model of EAE (39–41). This model shows progressive, sustained demyelination and associated axonal loss, and thus more closely reflects the clinical course of human RRMS than acute monophasic rodent EAE models (42). In the DA rat, oral teriflunomide (1, 3 or 10 mg/kg) dose dependently delayed disease onset and reduced neurological deficits and remained effective in different treatment scenarios (39, 40). Electrophysiological somatosensory evoked potential assessments showed that therapeutic treatment with teriflunomide improved several electrophysiological criteria. Thus, teriflunomide administered at disease onset prevented a decrease in waveform amplitude and an increase in latency to waveform initiation compared with vehicle-treated animals. Therapeutic dosing (i.e. at remission) improved evoked potential amplitude, decreased latency and enhanced recovery time in the CNS. Spinal cord histological assessments showed that teriflunomide (3 and 10 mg/kg) administered prophylactically or therapeutically at disease onset or disease remission, respectively, significantly reduced demyelination and axonal loss by up to 90% (39, 40). Teriflunomide also significantly reduced inflammation in the CNS as shown by a decrease in the number of B cells, T cells and macrophage infiltrates in the gracile fascicle (39, 40). In addition, prophylactic treatment with teriflunomide (10 mg/kg) significantly improved the number of surviving oligodendrocytes (as shown by GST-P immunostaining) in the gracile fascicle, potentially via a neuroprotective mechanism (41). Finally, MRI assessments [gadolinium (Gd)-enhanced T1 MRI] demonstrated the preservation of BBB integrity as measured by a decrease in MRI lesion load; thus, teriflunomide (3 mg/kg) led to a decrease in lesion load and a delay in BBB disruption compared to vehicle-treated animals, while the 10 mg/kg dose virtually eliminated Gd-enhanced lesion load indicating preservation of the BBB (39, 40).

Clinical pharmacokinetics

The pharmacokinetic (PK) profile of teriflunomide was established in 11 studies of healthy volunteers and one study of patients with MS (43). Following the administration of single oral doses to fasted healthy subjects, teriflunomide was rapidly absorbed with a median time to peak plasma concentration of 1–2 h, with absolute oral bioavailability approaching 100%. Peak plasma concentrations were dose proportional, indicating linear kinetics across the evaluated dose range (7–100 mg). Following administration with food, absorption was delayed by about 6 h; however, overall plasma exposure was similar in fasted and fed states. Preclinical studies demonstrate only limited penetration of teriflunomide across the BBB; instead teriflunomide is distributed predominantly in the periphery. Teriflunomide had a low volume of distribution at steady state (∼11 l) and was extensively (>99%) bound to plasma proteins, predominantly albumin. No single specific site or enzyme is responsible for the metabolism of teriflunomide; proposed biotransformation pathways include oxidation, hydrolysis and sulphate conjugation, involving several cytochrome P450 (CYP) enzymes and N-acetyltransferase. In a study of healthy subjects, multiple doses of rifampicin (a non-specific CYP and P-glycoprotein inducer) decreased teriflunomide area under the curve (AUC) and elimination half-life by ∼39% (44). Although in vitro studies indicate that teriflunomide may induce the activity of CYP3A, data from a drug interaction study with midazolam instead showed evidence of a weak inhibition of CYP3A (44). No significant PK interactions were reported after coadministration of teriflunomide with warfarin (a CYP2C9 substrate) (44). Following oral dosing of 14C-radiolabelled teriflunomide to healthy volunteers, unchanged drug was the primary component detectable in the circulation, with 37.5% of the dose excreted through faeces (predominantly as unchanged drug) and 22.6% through urine (primarily as the 4-trifluoro-methylaniline oxanilic acid metabolite), 3 weeks after administration. Plasma concentrations of teriflunomide declined slowly after oral administration, with an elimination half-life of 10–12 days. However, the elimination of teriflunomide from the circulation can be accelerated by administration of cholestyramine or activated charcoal (43). This is useful in situations of overdose or emerging toxicity and may differentiate teriflunomide from other oral DMTs, whose anti-inflammatory effects cannot be readily reversed (43). Finally, no differences for teriflunomide’s PK profile were apparent according to gender, age or hepatic impairment, and the PK profile was also similar in patients with MS.

Teriflunomide: clinical experience

Teriflunomide is being investigated in a comprehensive programme of clinical trials. This programme is evaluating the efficacy and safety of teriflunomide on a range of clinical and MRI endpoints when administered either as monotherapy or as an adjunctive therapy to ongoing treatment with one of the existing DMTs. All of the completed, ongoing and planned clinical trials for teriflunomide are summarized in Table 1.

Table 1.   Overview of completed and ongoing clinical trials with teriflunomide
Study description (study number)Patient populationStudy durationTreatment groupsEndpointsStatus
  1. ARR, annualised relapse rate; CIS, clinically isolated syndrome; EDSS, Expanded Disability Status Scale; HR-QOL, health-related quality of life; MRI, magnetic resonance imaging; MSFC, multiple sclerosis functional composite.

  2. aNumber of subjects enrolling into the long-term study following conclusion of the 36-week double-blind phase.

Monotherapy studies
A phase II study of the safety and efficacy of teriflunomide in MS with relapses
Phase II
HMR1726D/2001 (NCT00228163)
n = 179 Relapsing MS36 weeksPlacebo
Teriflunomide 7 mg
Teriflunomide 14 mg
Primary: Combined unique active lesions per scan
Secondary: Other MRI parameters, ARR, disability progression, safety and tolerability
Open-label extension of phase II study
Phase II
HMR1726D/2002 [LTS6048]
n = 147a Relapsing MS≥144 weeksCompleting subjects were eligible to enter the open-label extension study on their originally allocated teriflunomide dose; placebo-treated patients were re-randomised to either of the active treatment groupsPrimary: Safety and tolerability
TEMSO: Study of teriflunomide in reducing the frequency of relapses and accumulation of disability in patients with MS with relapses
Phase III
HMR1726D/3001 [EFC6049] (NCT00134563)
n = 1088 Relapsing MS108 weeksPlacebo
Teriflunomide, 7 mg
Teriflunomide, 14 mg
Primary: ARR
Secondary: Disability progression, MRI, fatigue, safety and tolerability
Data to be presented at ECTRIMS 2010
Open-label extension of TEMSO
Phase III
HMR1726D/3004 [LTS6050]
n = 556 Relapsing MS≥108 weeksCompleting subjects from the double-blind treatment phase of TEMSO are eligible to enter a 108-week open-label extension study; placebo-treated patients will be randomised to either active treatment groupsPrimary: Safety and tolerability
Secondary: EDSS, ARR, MRI
TOWER: An efficacy study of teriflunomide in patients with relapsing MS
Phase III
EFC10531 (NCT00751881)
n = 1110 planned
Relapsing MS
≥48 weeksPlacebo
Teriflunomide, 7 mg
Teriflunomide, 14 mg
Primary: ARR
Secondary: Disability progression
TENERE: A study comparing the effectiveness and safety of teriflunomide and interferon beta-1a in patients with relapsing MS
Phase III
EFC10891 (NCT00883337)
Relapsing MS
≥48 weeksTeriflunomide, 7 mg
Teriflunomide, 14 mg
Interferon beta-1a, 44 μg three times per week
Primary: Time to failure (defined as the first occurrence of relapse or permanent study treatment discontinuation for any cause (whichever comes first)
Secondary: ARR
TOPIC: Phase III study with teriflunomide vs placebo in patients with first clinical symptom of MS
Phase III
HMR1726D/3005 [EFC6260] (NCT00622700)
n = 780 planned
Early MS/CIS
2 yearsPlacebo
Teriflunomide, 7 mg
Teriflunomide, 14 mg
Primary: Conversion to clinically definite MS
Secondary: ARR, MRI, disability progression, safety and tolerability
Adjunctive therapy studies
Pilot study of teriflunomide as adjunctive therapy to IFN-β in subjects with MS
Phase II
HMR1726D/2003 [PDY6045]
n = 116
Patients with relapsing MS receiving a stable dose of IFN-β
24 weeksPlacebo
Teriflunomide, 7 mg
Teriflunomide, 14 mg
All treatments are added to ongoing therapy with a stable dose of IFN-β
Primary: Safety and tolerability
Secondary: MRI, ARR
Pilot study of teriflunomide as adjunctive therapy to glatiramer acetate (GA) in subjects with MS
Phase II
HMR1726D/2004 [PDY6046] (NCT00475865)
n = 123
Patients with relapsing MS receiving a stable dose of GA
24 weeksPlacebo
Teriflunomide, 7 mg
Teriflunomide, 14 mg
All treatments are added to ongoing therapy with a stable dose of GA
Primary: Safety and tolerability
Secondary: MRI, ARR
Long-term safety of teriflunomide when added to IFN-β or GA in patients with MS
Extension of Phase II adjunctive therapy studies
HMR1726D/2005 LTS6047 (NCT00811395)
Patients with relapsing MS receiving a stable dose of IFN-β or GA
48 weeksCompleting subjects from the double-blind treatment phase of the two pilot adjunctive therapy studies at week 24 are eligible to enter a 24-week extension study; blind maintained during extensionPrimary: Safety and tolerability
Secondary: MRI, ARR, disability progression

Clinical efficacy: monotherapy– Teriflunomide was evaluated in a 36-week randomized, double-blind, placebo-controlled study of 179 patients with relapsing MS (RRMS and SPMS with relapses) (45). This ‘proof-of-concept’ study enrolled patients (18–65 years) with clinically definite MS and Expanded Disability Status Scale (EDSS) scores below 6.0, with at least two relapses in the preceding 3 years and at least one in the previous year. Patients were randomized to once-daily placebo (n = 61), teriflunomide 7 mg (n = 61) or teriflunomide 14 mg (n = 57). The primary endpoint was the number of combined unique active lesions per scan [a combination of T2/proton density and gadolinium (Gd)-enhanced T1 lesions]. Additional MRI and clinical measures [e.g. MS relapse, annualized relapse rate (ARR), disability progression] were evaluated as secondary endpoints.

The primary endpoint of the study was met; teriflunomide significantly reduced MRI activity compared with placebo. Thus, the median number of combined unique active lesions per scan was 0.5, 0.2 and 0.3 with placebo, teriflunomide, 7 and 14 mg, respectively [relative risk reduction in MRI activity >61% for both doses (P < 0.03 and P < 0.001 for 7 and 14 mg, vs placebo, respectively)]. These effects were apparent as early as 6 weeks, reached statistical significance by 12 weeks and were maintained throughout the study (Fig. 3). A significant reduction in the number of new or enlarging T2 lesions and fewer enhancing T1 lesions was also reported.

Figure 3.

 Cumulative number of combined unique active lesions with teriflunomide in relapsing MS.

Although this trial was designed to evaluate MRI endpoints, there was also a trend towards lower ARRs with teriflunomide compared with placebo, but the differences did not reach significance (0.81, 0.58, 0.55 for placebo, teriflunomide, 7 and 14 mg, respectively; relative risk reductions: 28% and 32%). There was also a trend towards more relapse-free patients in the 14 mg teriflunomide group compared with placebo (77% vs 62%; = 0.098), while fewer patients in this group required steroids for disease exacerbations (14% vs 23%). The proportion of patients with increase in disability was also significantly lower in the 14 mg group compared with placebo-treated patients (7.4% vs 21.3%; P < 0.04).

An open-label extension was initiated upon completion of the double-blind phase (46). Patients originally allocated teriflunomide continued treatment, while those allocated placebo were re-randomized to teriflunomide. A total of 147 patients entered the extension phase (teriflunomide 7 mg: n = 81; teriflunomide 14 mg: n = 66). Efficacy data in patients completing 144 weeks of treatment (n = 114) were compared to the baseline of the extension phase. Patients switching from placebo to active treatment with teriflunomide had significant decreases in the number of combined unique active lesions at week 144 (relative risk reductions: 65% and 85% for teriflunomide, 7 and 14 mg; = 0.02 for both vs baseline). Patients remaining on teriflunomide experienced no further change in the number of active lesions during the open-label extension phase. ARRs were similar in both groups (0.4 relapses per year) as was the proportion of patients without relapse at week 144 (54%). In summary, these observations demonstrate that longer term exposure to teriflunomide does not lead to any decline in patient response with regard to MRI burden and clinical endpoints. A broader Phase 3 evaluation of teriflunomide adopting clinical outcomes as primary endpoints in larger populations with a longer duration of treatment is eagerly anticipated. TEMSO – Teriflunomide in Reducing the Frequency of Relapses and Accumulation of Disability in Patients with Multiple Sclerosis – will be the first such trial to conclude its placebo-controlled phase in the second quarter of 2010.

Clinical efficacy: adjunctive therapy– Two randomized, double-blinded, placebo-controlled, adjunctive therapy studies have evaluated the safety and efficacy of teriflunomide as an adjunct to ongoing IFN-β or GA therapy (47, 48).

In the first study, 116 patients with relapsing MS already receiving a stable dose of IFN-β were randomized to teriflunomide, 7 or 14 mg, or placebo, for 24 weeks (47). Teriflunomide improved disease control beyond that achieved with IFN-β therapy alone. Thus, the number and volume of T1-Gd lesions were reduced in both teriflunomide groups (7 mg: 56% and 14 mg: 81%; both P < 0.001 vs placebo) and a greater proportion of patients remained free of T1-Gd lesions with teriflunomide than with placebo (placebo: 57.9%, 7 mg: 69.4% and 14 mg: 81.6%).

The second study adopted a similar design but evaluated teriflunomide added to concurrent therapy with a stable dose of GA (48). A total of 123 patients with relapsing MS already receiving GA were randomized to once-daily teriflunomide therapy (7 or 14 mg) or placebo. The addition of teriflunomide to GA improved disease control compared with GA therapy alone. Thus, compared to placebo, the number of T1-Gd lesions were reduced in the 7 mg group (= 0.011), and the T1-Gd lesion volume was reduced in the 14 mg group (= 0.039).

These interesting results suggest that there is a potential for the use of teriflunomide in adjunctive therapy and that further investigations should be considered to fully establish the clinical benefit of this combination approach to treatment.

Safety and tolerability– From the clinical experience gathered to date, teriflunomide has an acceptable safety and tolerability profile, with no significant safety concerns. Notably, there was no evidence of opportunistic infections or impaired immune surveillance in any patient in the phase 2 study described previously, with no deaths reported (45). Adverse events that occurred during the double-blind phase of this study were predominantly minor and occurred at a similar frequency across all treatment groups. Adverse events more frequently reported with teriflunomide than with placebo included nasopharyngitis, alopecia, nausea, increases in alanine aminotransferase (ALT), paraesthesia, back and limb pain, diarrhoea and arthralgia. An apparent dose-dependent trend in the incidence of alopecia, nausea, paraesthesia, back pain and diarrhoea was reported. There was also a higher frequency of treatment discontinuation owing to adverse events in the higher dose teriflunomide group (14.0%) compared with both placebo (6.6%) and the 7 mg (4.9%) groups. Serious adverse events were evenly distributed throughout the three treatment groups (11.5%, 8.2% and 12.3%, in the placebo, teriflunomide 7 mg and 14 mg groups, respectively). The most frequently observed serious adverse events were abnormal liver function tests or isolated elevations in ALT, hepatic dysfunction, neutropenia, elevations in creatine kinase levels and trigeminal neuralgia. However, serious adverse events related to abnormal hepatic function were equally as frequent or more frequent in patients receiving placebo than in those who received teriflunomide (placebo: 5%; teriflunomide 7 mg: 0%; teriflunomide 14 mg: 5%). Although leukocyte decreases were more frequent in the teriflunomide groups, no patients discontinued therapy owing to leukopenia or neutropenia, and infections were comparable across the treatment groups.

Safety data from the open-label extension phase of the study confirmed the safety profile of teriflunomide observed in the double-blind treatment phase without the emergence of any new safety concerns. Thus, the incidence of treatment-emergent adverse events (TEAEs) and the number of serious TEAEs was similar across treatment groups, and the overall drop-out rate was <10% per year. Although a higher frequency of hepatic enzyme elevation was observed, any effects on ALT remained stable with up to 144 weeks of continuous treatment (46).

Finally, when teriflunomide was added to ongoing IFN-β or GA therapy over a 6-month treatment period, the safety profile of teriflunomide reflected that observed in the phase 2 monotherapy studies (47, 48).

The safety experience with teriflunomide to date can be supplemented by post-marketing experience with the prodrug, leflunomide. In excess of 1.5 million patient-years of leflunomide exposure has accumulated since its licensure for rheumatoid arthritis in 1998 (44), and experience with its use provides some confidence that teriflunomide will have at least as good a safety profile in clinical practice.

The teriflunomide clinical development plan

An extensive clinical development programme is already underway to evaluate the efficacy, safety and tolerability of teriflunomide in MS (Table 1). Over 3000 patients will be enrolled across various clinical trials to evaluate teriflunomide as monotherapy. In addition, the effects of early intervention with teriflunomide in patients with a first event suggestive of demyelination and MRI characteristics suggesting a risk of MS development are being explored in an ongoing pivotal clinical trial. This extensive clinical development programme constitutes one of the widest programs of any of the new oral disease-modifying agents; it will address a range of issues relevant for the successful treatment of MS and, it is hoped, will bring a novel therapeutic approach for MS to the market.


A number of oral disease-modifying treatments are currently being investigated in clinical trials for the treatment of RRMS. Teriflunomide is one such oral agent that is well advanced in terms of clinical development. Although its precise mechanism of action is still under investigation, teriflunomide is thought to act by inhibiting peripheral activation of T-lymphocytes, thereby reducing their infiltration into the CNS. Infiltration of autoreactive T cells into the CNS is a pivotal event that triggers a cascade of immune reactions which initiate oligodendrocyte apoptosis ultimately leading to myelin damage. Based on this model of MS pathogenesis and the proposed mechanism of action, we could speculate that teriflunomide may be most effective between the early stage of the disease and the relapsing–remitting stage, at a time when autoimmune responses and subsequent inflammatory disease may be controlled. The decrease in active MRI lesions observed in clinical trials would appear to confirm this hypothesis.

In summary, based on currently available data, teriflunomide appears to have a favourable benefit/risk ratio in RRMS, and as such, represents a promising new treatment for MS.

Author disclosures

RG has received speaker’s and consulting honoraria from sanofi-aventis. JW has served on advisory boards and data monitoring committees, has had consulting agreements, or received speaker honoraria from Acorda Therapeutics, Acetilon, Antisense Therapeutics Ltd., Bayer HealthCare Pharmaceuticals, the Consortium of Multiple Sclerosis Clinics Inc., Facet Biotech, Eli Lilly Co., EMD Serono, Genentech Inc, the National Multiple Sclerosis Society, Novartis Pharmaceuticals Corp., sanofi-aventis, Teva Pharmaceuticals, Ltd., UCB, the University of South Florida and the University of Texas Medical Branch; received royalties for out-licensed monoclonal antibodies through the University of Texas Health Science Center at Houston to Millipore (Chemicon International) Corporation since 1993; received research or contractual support from the Clayton Foundation for Research, the NIH [2 U01 NS045719-06 (PI of the subcontract to UTHSCH for image analysis), 2RO1-EB002095-06A1 (Co-investigator), and sanofi-aventis; and served as an Associate Editor for ACP Medicine, BC Decker.