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Teriflunomide (Aubagio®) for the treatment of multiple sclerosis

Experimental Neurology

Abstract

Teriflunomide (Aubagio®) is a once-daily oral immunomodulatory disease modifying therapy (DMT) presently approved in several regions, including Europe, North America, Latin America and Australia, for the treatment of relapsing forms of multiple sclerosis (RMS; RRMS). The therapeutic mode of action of teriflunomide in MS continues to be investigated. This review summarizes the main efficacy and safety results of the clinical trial program leading to teriflunomide's approval, highlights a number of practical clinical considerations, and overviews its presumed therapeutic mode of action (MOA) based on pharmacokinetic and pharmacodynamic observations and the growing body of teriflunomide-related in vitro, pre-clinical (animal model), and in vivo human studies.

Highlights

 

  • Once-daily, oral immunomodulatory disease modifying therapy, for relapsing MS
  • Demonstrated ability to limit MS relapses and delay disability progression
  • Generally safe and well-tolerated, may induce liver enzymes; pregnancy category ‘X’
  • Known inhibitor of ‘de novo’ pyrimidine synthesis pathway, sparing salvage pathway
  • Therapeutic MOA thought to reflect selective impact on activated immune cells

Keywords: Multiple sclerosis, Immune modulation, Treatment, Aubagio, Teriflunomide, Leflunomide.

Introduction

Teriflunomide (Aubagio®) is the active metabolite of leflunomide (Arava®), which was approved in 1998 by the US FDA for the treatment of adults with rheumatoid arthritis (RA) ( Osiri et al., 2003 ). Based on promising results of the Phase II program in MS (Bar-Or et al, 2013a, Confavreux et al, 2012, Freedman et al, 2011, Freedman et al, 2012, O'Connor et al, 2006, and Wingerchuk and Carter, 2014), teriflunomide's efficacy, safety and tolerability profiles have been established in patients with relapsing MS through several Phase III clinical trials including TEMSO (Miller et al, 2012, O'Connor et al, 2011, O'Connor et al, 2013, and Wolinsky et al, 2013), TOWER (Confavreux et al, 2014 and Kieseier and Wiendl, 2014), TENERE ( Vermersch et al., 2014 ) and TERACLES ( Freedman et al., 2014 ), as well as the TOPIC study of patients with a first clinical episode consistent with MS ( Miller et al., 2014 ). As a result of this development program, teriflunomide has been approved to date as a once-daily oral disease modifying therapy (DMT) for patients with relapsing forms of MS (RMS, RRMS) in several regions, including Europe, North America, Latin America and Australia (Brunetti et al, 2013, Oh and O'Connor, 2013, and Warnke et al, 2013). The therapeutic mode of action of teriflunomide in MS is not fully elucidated (Reviewed in: Bar-Or et al., 2014 ). Biochemically, it acts as an inhibitor of dihydroorotate-dehydrogenase (DHODH), a mitochondrial enzyme involved in the de novo synthesis of pyrimidines, and particularly active in proliferating cells. Teriflunomide has been shown in animal models as well as in patients, to selectively reduce the activity of proliferating T cells and B cells, providing evidence for its anti-inflammatory properties. At the same time, teriflunomide appears to have little or no effect on homeostatically proliferating immune cells which are able to generate sufficient pyrimidine pools through an alternate (‘salvage’) pathway that is independent of DHODH ( Figure 1 ). Together, these findings indicate that teriflunomide generally acts as a cytostatic (rather than cytotoxic) agent to immune cells. In keeping with this, results of the Phase II and III clinical trials, as well as analyses of vaccine studies in subjects treated with teriflunomide, provide in vivo evidence that teriflunomide on one hand has immune modulatory effects capable of limiting new inflammatory disease activity in MS patients, while not substantially limiting the ability of treated individuals to mount effective protective immune responses. This review will first summarize main safety and efficacy results from the (Phase II and III) clinical trial program leading to teriflunomide's approval (see Table for summary), outline practical clinical considerations relevant for its use, and consider its presumed therapeutic mode of action based on studies in both humans and animal models.

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Fig. 1 Teriflunomide's presumed mechanisms of action (MOA) in MS. Figure licensed under a Creative Commons Attribution license (CC BY-NC 2.5) from: Teriflunomide and its Mechanism of Action in Multiple Sclerosis. Bar-Or A, Pachner A, Menguy-Vacheron F, Kaplan J, Wiendl H. Drugs. 2014;74:659-74.

Phase II studies of teriflunomide in MS

Teriflunomide compared to placebo

The Phase II study titled: ‘Safety and Efficacy of Teriflunomide (HMR1726) in Multiple Sclerosis With Relapses (ClinicalTrials.gov identifier: NCT01487096)’ ( O'Connor et al., 2006 ) was a multi-center, randomized, placebo-controlled and double blinded, parallel group design study that recruited 179 patients with relapsing forms of MS (157 RRMS; 22 secondary progressive MS [SPMS] with relapses). Patients were randomized to receive either placebo, teriflunomide 7 mg or teriflunomide 14 mg over 36 weeks with the primary outcome defined as the number of cumulative unique active lesions (CUALs). Treatment was overall well tolerated with similar numbers of adverse events and serious adverse events noted in all treatment groups. The median number of CUALs per scan was 0.5, 0.2, and 0.3 in the placebo, teriflunomide 7 mg/day (p < 0.03 vs placebo), and teriflunomide 14 mg/day (p < 0.01 vs placebo) groups over the 36-week double-blind treatment phase. Teriflunomide treatment also significantly reduced the number per scan of T1 gadolinium-enhancing (T1 Gd +) lesions, and new or enlarging T2 lesions. T2 disease burden accumulation over time was also significantly reduced, with a trend towards lower annualized relapse rate and fewer relapsing patients in the 14 mg/day group compared to placebo. Compared to patients receiving placebo, significantly fewer patients receiving teriflunomide 14 mg/day demonstrated increased disability during the core double blind treatment phase. Of the patients completing the core study, 147 entered an open-label extension; those who were teriflunomide-treated continued their assigned dose, while placebo-treated patients were re-allocated to either 7 mg or 14 mg of teriflunomide, daily. Analysis of extension phase data was reported ( Confavreux et al., 2012 ) at a median follow-up duration of 7.1 years (range: 0.05–8.5 years), from the start of the core study. Approximately 42% of patients discontinued treatment—19% due to ‘treatment-emergent adverse events (TEAE’). The most common TEAE included mild infections, fatigue, diarrhea or sensory disturbances. There were no serious opportunistic infections and none of the discontinuations were due to infection. Asymptomatic increases in alanine aminotransferase (≤ 3 × upper limit of normal (ULN) were common (approximately 60% with both the 7 mg and 14 mg doses). Increases of > 3 × ULN occurred in approximately 12% of patients at both doses. Mild decreases were noted in neutrophil counts, with none leading to discontinuation and the incidence of malignancies was no different than expected in the general population. Throughout the extension phase, annualized relapse rates remained low, disability progression appeared minimal and a dose-dependent benefit for several MRI parameters was noted in the teriflunomide 14 mg treated group. Ongoing monitoring of this Phase II cohort continues (NCT00228163).

Teriflunomide as adjunctive therapy

Teriflunomide was assessed in two separate studies as an adjunct therapy to either IFNβ or glatiramer acetate (GA): The clinical trial of teriflunomide as adjunctive therapy to IFNβ (NCT00489489) was a randomized, double-blinded, placebo-controlled parallel-group study of 24-week duration in patients with relapsing MS who were stably treated at enrollment for at least half a year with IFNβ ( Freedman et al., 2012 ). The intent-to-treat population included 37 patients randomized to adjunctive treatment with teriflunomide 7 mg daily, 38 to adjunctive treatment with teriflunomide 14 mg daily, and 41 patients to adjunctive placebo. Teriflunomide was overall well tolerated with a low incidence of TEAEs that was similar across groups. Significant reductions in the relative risk of developing T1 Gd + lesions were observed in patients receiving adjunct therapy with teriflunomide 7 mg (p = 0.0009) and teriflunomide 14 mg (p < 0.0001) compared to patients receiving placebo and IFNβ. There was no apparent impact on relapse rates in this short study. The study of teriflunomide as an adjunctive therapy to glatiramer acetate (GA) (NCT00475865) used a similar design including the profile of recruited patients with relapsing MS, the study size, duration and major outcome measures ( Freedman et al., 2011 ). A reduction in the relative risk of developing T1 Gd + lesions was observed in patients receiving adjunct therapy with teriflunomide 7 mg (p = 0.011) but not in patients receiving teriflunomide 14 mg. There was again no observable effect on relapses. There were again no particular safety issues in either of doses of teriflunomide used in combination with GA. Together, the phase II studies of teriflunomide in combination with either IFNβ or GA provided some early efficacy data suggesting that teriflunomide may enhance the benefit of either of these very established therapies, as well as a reassuring safety and tolerability profile ( Wingerchuk and Carter, 2014 ). These results also set the stage for design of the Phase III TERACLES study, described below.

Phase III studies of teriflunomide in MS

The TEMSO study (NCT00134563)

In this Phase III, double-blind, placebo-controlled, multicenter trial, 1088 patients with RRMS and EDSS scores ≤ 5.5, experiencing at least two relapses in the 2 years prior (or at least one relapse in the year prior) to study entry, were randomized (1:1:1) to either placebo, or to teriflunomide at either 7 mg or 14 mg, daily ( O'Connor et al., 2011 ). The primary endpoint of annualized relapse rate (ARR) at week 108 was significantly decreased in both teriflunomide arms compared to placebo (ARR for placebo: 0.54, versus 0.37 for both teriflunomide treatment arms,p < 0.001 for both). In addition, teriflunomide treatment was associated with decreased proportions of patients experiencing 12-week confirmed disability progression (27.3%, 21.7%, 20.2% for placebo, 7 mg, 14 mg arms, respectively;p = 0.0835 for 7 mg vs placebo,p = 0.0279 for 14 mg vs placebo). Compared to placebo, multiple MRI measures were also improved in the 7 mg and 14 mg teriflunomide treatment groups, including decreased total brain MRI T2 lesion volumes (p = 0.03 andp < 0.001, respectively), fewer T1 Gd + lesions (p < 0.001 for both comparisons), and fewer unique active lesions (p < 0.001 for both comparisons). With respect to adverse events, diarrhea, nausea, and hair thinning were more common with teriflunomide than with placebo. The incidence of elevated alanine aminotransferase to levels ≥ 1 × ULN was higher with teriflunomide at 7 mg (54%) and 14 mg (57.3%) compared to placebo (35.9%), though the incidence of levels that were ≥ 3 × ULN was between 6 and 7% in all three groups. Serious infections were reported in 1.6% (teriflunomide 7 mg), 2.5% (teriflunomide 14 mg) and 2.2% (placebo). Pre-specified sub-group analyses of the TEMSO study ( Miller et al., 2012 ) considered ARR and disability progression by baseline demographics (gender, race, age), disease characteristics (EDSS levels, relapse history, and MS subtype), MRI parameters (T1 Gd + lesions, total lesion volume) and prior use of MS therapies. Reductions in ARR and disability progression with teriflunomide treatment compared to placebo were found to be consistent across subgroups. Secondary and exploratory MRI outcomes from the TEMSO trial were reported separately ( Wolinsky et al., 2013 ). After 108 weeks, increases in total brain lesion volumes (as a measure of disease burden) were 39.4% (p = 0.0317) and 67.4% (p = 0.0003) lower in the 7 mg and 14 mg teriflunomide groups compared to placebo. A dose effect was evident on several additional MRI measures, and was consistent across pre-defined study subgroups. A post hoc analysis of the Phase III TEMSO data evaluated the impact of teriflunomide on relapse-related neurological sequelae and utilization of healthcare resources ( O'Connor et al., 2013 ). Sequelae included relapses resulting in changes in disability or functional system (EDSS/FS) scores, relapses with investigator-defined sequelae, relapses requiring hospitalization or intravenous (IV) corticosteroids, emergency medical facility visits (EMFV), and nights hospitalized. Compared to placebo, teriflunomide treatment decreased annualized rates of relapses with EDSS/FS sequelae (teriflunomide 7 mg: 32 % reduction,p = 0.0019; teriflunomide 14 mg: 36 %,p = 0.0011); relapses with investigator-defined sequelae (7 mg: 25 %,p = 0.071; 14 mg: 53 %,p < 0.0001); relapses leading to hospitalization (7 mg: 36 %,p = 0.015); 14 mg: 59 %,p < 0.0001), and of relapses requiring IV corticosteroids (7 mg: 29%,p = 0.001); 14 mg: 34 %,p < 0.0003). Teriflunomide-treated patients also spent fewer nights in hospital for relapse (p < 0.01), while teriflunomide 14 mg decreased annualized rates of all hospitalizations (p = 0.01) and of EMFV (p = 0.004).

The TOWER study (NCT00751881)

This Phase III randomized, double-blind, placebo-controlled, study enrolled 1169 patients aged 18–55 years with relapsing MS, EDSS of up to 5.5, and at least one relapse in the prior 12 months (or at least two relapses in the prior 24 months), at 189 sites in 26 countries (Confavreux et al, 2014 and Kieseier and Wiendl, 2014). In the intention to treat population, patients were assigned (1:1:1) to oral place"bo (n = 388), or teriflunomide at either 7 mg (407), or 14 mg (370), daily. At the end of the study (48 weeks after last patient entered), the primary outcome measure of ARR was significantly lower in patients treated with both teriflunomide 7 mg (ARR = 0.39 [0.33–0.46];p = 0.0183) and teriflunomide 14 mg (0.32 [0.27–0.38];p = 0.0001) compared to placebo (0.50 [95% CI 0.43–0.58]), essentially confirming the observations from the TEMSO study in which ARR was also favorably impacted at both doses of teriflunomide. Teriflunomide 14 mg also reduced the risk of sustained accumulation of disability in the TOWER study compared to placebo (p = 0.0442); though teriflunomide 7 mg had no effect. Similar to other studies, the most common adverse events included increases in alanine aminotransferase (8% in the placebo group compared to 11% and 14% in the teriflunomide 7 mg and 14 mg groups, respectively; hair thinning (4% vs 10% and 13%, respectively); and headache (11% vs 15% and 12%, respectively. No differences were seen in the frequencies of serious adverse events across the three groups. Overall, these results indicated that treatment with teriflunomide resulted in lower relapse rates, and at the 14 mg dose also with less disability accumulation, compared with placebo, with similar safety and tolerability profiles as reported in other studies.

The TENERE study (NCT00883337)

In this randomized, rater-blinded, Phase III study, over 320 patients with relapsing multiple sclerosis and EDSS scores ≤ 5.5, were randomized (1:1:1) to oral teriflunomide 7- or 14 mg, or subcutaneous IFNβ-1a (Rebif ®; 44 μg) ( Vermersch et al., 2014 ). No differences between groups were noted for the primary endpoint, which was defined as either occurrence of relapse or permanent treatment discontinuation for any reason. There were also no apparent differences in ARR between teriflunomide 14 mg and IFNβ-1a groups, though the ARR appeared higher with teriflunomide 7 mg. Fatigue was more common in the IFNβ-1a treated group and treatment satisfaction scores were better in the teriflunomide treated groups. The teriflunomide safety and tolerability profiles were consistent with other studies.

The TERACLES study (NCT01252355)

This Phase III study was designed to evaluate the safety and efficacy of teriflunomide when added to any IFNβ therapy. The study which aimed to randomize over 1400 patients was interrupted early because of concerns over feasibility and costs of retaining patients on two DMTs over an extended period. Early results based on 178 patients randomized to teriflunomide 7 mg + IFNβ, 179 to teriflunomide 14 mg + IFNβ and 175 to placebo + IFNβ, did not capture significant effects of teriflunomide addition on ARR, though decreases in the relative risk of developing T1 Gd + brain lesions were observed in the teriflunomide 14 mg + IFNβ group (p = 0.0061), as was a trend towards such an effect in the teriflunomide 14 mg + IFNβ group (p = 0.0618), compared to the placebo + IFNβ group ( Freedman et al., 2014 ).

The TOPIC study (NCT00622700)

This double blind, placebo-controlled, parallel group, Phase III Study, randomized (1:1:1) 618 patients with a single clinical episode suggestive of MS to placebo or to teriflunomide 7 mg or 14 mg arms ( Miller et al., 2014 ). The main objective of this study was to demonstrate that early intervention with teriflunomide in such patients will decrease disease activity thereby delaying the diagnosis of clinically definite MS. Compared to placebo treatment, time to relapse confirming the diagnosis of MS was increased with both teriflunomide 7 mg (p= 0.0271) and teriflunomide 14 mg (p= 0.0087). These effects were more evident when either time to clinical relapse or to development of new MRI lesion (T1 Gd + or new T2) was deemed MS-defining (teriflunomide 7 mg,p = 0.002; teriflunomide 14 mg,p = 0.0003).

Efficacy and safety summary based on teriflunomide clinical trial program in MS

The body of efficacy data generated in its Phase II and Phase III clinical trial program in MS ( Table 1 ), points to teriflunomide's ability to decrease relapses and limit (12-week confirmed) sustained progression of disability compared to placebo in patients with relapsing forms of MS (reviewed in 17–19). A convergence of clinical and imaging outcomes points to a therapeutic dose–response, with oral teriflunomide at 14 mg daily being superior on several efficacy outcomes compared to the 7 mg daily dosing.

Table 1 Teriflunomide (Phase II and Phase III) clinical trials.

Study Study design and population a Regimen b Key efficacy outcomes
Phase II
Phase II study, NCT014870961 • R, DB, PC, PG

• Duration: 36 weeks

• Patients with RRMS or SPMS with relapses

N = 179
Teriflunomide 7 mg (n = 61)

Teriflunomide 14 mg (n = 57)

Placebo (n = 61)
Number of combined unique active lesions c

Relative reduction vs placebo, %

 Teriflunomide 7 mg: 61.1, p < 0.03

 Teriflunomide 14 mg: 61.3, p < 0.01

Adjusted annualized relapse rate, Mean (± SD)

 Teriflunomide 7 mg: 0.58 (0.85) d

 Teriflunomide 14 mg: 0.55 (1.12) d

 Placebo: 0.81 (1.22)
Teriflunomide as an adjunctive therapy to IFNβ, NCT004894892 • R, DB, PC, PG

• Duration: 24 weeks

• Patients with RMS treated for ≥ 26 weeks with IFNβ

N = 118
Teriflunomide 7 mg + IFNβ (n = 37)

Teriflunomide 14 mg + IFNβ (n = 38)

Placebo + IFNβ (n = 41)
Adjusted Gd-enhancing T1-lesions per scan

Relative risk (95% CI) vs placebo + IFNβ

 Teriflunomide 7 mg + IFNβ: 0.174 (0.062, 0.487), p = 0.0009

 Teriflunomide 14 mg + IFNβ: 0.156 (0.080, 0.304), p < 0.0001

Adjusted annualized relapse rate

Relative risk (95% CI) vs placebo + IFNβ

 Teriflunomide 7 mg + IFNβ: 1.079 (0.342, 3.403), p = 0.8968

 Teriflunomide 14 mg + IFNβ: 0.420 (0.085, 2.063), p < 0.2852
Teriflunomide as an adjunctive therapy to GA, NCT004758653 • R, DB, PC, PG

• Duration: 24 weeks

• Patients with RMS treated for ≥ 26 weeks with GA

N = 123
Teriflunomide 7 mg + GA (n = 42)

Teriflunomide 14 mg + GA (n = 40)

Placebo + GA (n = 41)
Adjusted Gd-enhancing T1-lesions per scan

Relative risk (95% CI) vs placebo + GA

 Teriflunomide 7 mg + GA: 0.298 (0.117, 0.757), p = 0.0110

 Teriflunomide 14 mg + GA: 0.464 (0.179, 1.208), p = 0.1157

Adjusted annualized relapse rate

Relative risk (95% CI) vs placebo + GA

 Teriflunomide 7 mg + GA: 0.655 (0.258, 1.666), p = 0.3742

 Teriflunomide 14 mg + GA: 1.362 (0.641, 2.897), p = 0.4215
TERIVA NCT014033764 • PG

• Duration: 28 days

• Patients with RMS treated for ≥ 6 months with teriflunomide 14 mg, teriflunomide 7 mg, or IFNβ

N = 122 e
Teriflunomide 7 mg (n = 40)

Teriflunomide 14 mg (n = 39)

IFNβ (n = 43)
Proportion of patients with post vaccination influenza antibody titers ≥ 40 at Day 28, % (90% CI)

Influenza strain H1N1

 Teriflunomide 7 mg: 97.5 (93.4, 100.0)

 Teriflunomide 14 mg: 97.4 (93.3, 100.0)

 IFNβ: 97.7 (93.9, 100.0)

Influenza strain H3N2

 Teriflunomide 7 mg: 90.0 (82.2, 97.8)

 Teriflunomide 14 mg: 76.9 (65.8, 88.0)

 IFNβ: 90.7 (83.4, 98.0)

Influenza strain B

 Teriflunomide 7 mg: 97.5 (93.4, 100.0)

 Teriflunomide 14 mg: 97.4 (93.3, 100.0)

 IFNβ: 93.0 (86.6, 99.4)
 
Phase III
TEMSO, NCT001345635 • R, DB, PC, PG

• Duration: 108 weeks

• Patients with RMS

N = 1088
Teriflunomide 7 mg (n = 365)

Teriflunomide 14 mg (n = 358)

Placebo (n = 363)
Adjusted annualized relapse rate

Relative risk (95% CI) vs placebo

 Teriflunomide 7 mg: 0.688 (0.563, 0.839), p = 0.0002

 Teriflunomide 14 mg: 0.685 (0.554, 0.847), p = 0.0005

Disability progression sustained for 12 weeks

Hazard ratio (95% CI) vs placebo

 Teriflunomide 7 mg: 0.763 (0.555, 1.049), p = 0.0835

 Teriflunomide 14 mg: 0.702 (0.506, 0.973), p = 0.0279
TOWER, NCT007518816 • R, DB, PC, PG

• Duration: variable, ending 48 weeks after last patient randomised

• Patients with RMS

N = 1169
Teriflunomide 7 mg (n = 407)

Teriflunomide 14 mg (n = 370)

Placebo (n = 388)
Adjusted annualized relapse rate

Relative risk (95% CI) vs placebo

 Teriflunomide 7 mg: 0.777 (0.630, 0.958), p = 0.0183

 Teriflunomide 14 mg: 0.637 (0.512, 0.793), p = 0.0001

Disability progression sustained for 12 weeks

Hazard ratio (95% CI) vs placebo

 Teriflunomide 7 mg: 0.955 (0.677, 1.347), p = 0.7620

 Teriflunomide 14 mg: 0.685 (0.467, 1.004), p = 0.0442
TOPIC, NCT006227007 • R, DB, PC, PG

• Duration: 108 weeks

• Patients with a first clinical episode consistent with MS

N = 618
Teriflunomide 7 mg (n = 203)

Teriflunomide 14 mg (n = 214)

Placebo (n = 197)
Time to relapse confirming CDMS

Hazard ratio (95% CI) vs placebo

 Teriflunomide 7 mg: 0.628 (0.416, 0.949), p = 0.0271

 Teriflunomide 14 mg: 0.574 (0.379, 0.869), p = 0.0087

Time to relapse or occurrence of new MRI lesion f

Hazard ratio (95% CI) vs placebo

 Teriflunomide 7 mg: 0.686 (0.540, 0.871), p = 0.0020

 Teriflunomide 14 mg: 0.651 (0.515, 0.822), p = 0.0003
TENERE, NCT008833378 • R, DB (teriflunomide doses), OL (IFNβ-1a), PG, RB

• Duration: variable, ending 48 weeks after last patient randomized

• Patients with RMS

N = 324
Teriflunomide 7 mg (n = 109)

Teriflunomide 14 mg (n = 111)

IFNβ-1a (n = 104)
Time to failure

Hazard ratio (95% CI) vs IFNβ-1a

 Teriflunomide 7 mg: 1.122 (0.752, 1.674), p = 0.5190

 Teriflunomide 14 mg: 0.861 (0.564, 1.314), p = 0.5953

Adjusted annualized relapse rate

Relative risk (95% CI) vs IFNβ-1a

 Teriflunomide 7 mg: 1.897 (1.050, 3.426), p = 0.0339

 Teriflunomide 14 mg: 1.197 (0.623, 2.299), p = 0.5896
TERACLES,

NCT012523559
• R, DB, PC, PG

• Duration: variable, planned to end 48 weeks after last patient randomized

• Patients with RMS treated for ≥ 6 months with IFNβ

N = 534
Teriflunomide 7 mg + IFNβ (n = 178)

Teriflunomide 14 mg + IFNβ (n = 179)

Placebo + IFNβ (n = 175)
Adjusted annualized relapse rate

Relative risk (95% CI) vs placebo + IFNβ

 Teriflunomide 7 mg + IFNβ: 0.812 (0.502, 1.312), p = 0.3940

 Teriflunomide 14 mg + IFNβ: 0.797 (0.516, 1.232), p = 0.3076

Adjusted Gd-enhancing T1-lesions per scan

Relative risk (95% CI) vs placebo + IFNβ

 Teriflunomide 7 mg + IFNβ: 0.474 (0.217, 1.037), p = 0.0618

 Teriflunomide 14 mg + IFNβ: 0.292 (0.121, 0.704), p = 0.0061

a Randomized population.

b Intent to treat population.

c Newly enhancing/persistently Gd-enhancing T1 lesions and/or new/newly enlarging/persistently enlarging T2 hyperintense lesions.

d Non-significant reduction vs placebo.

e Per-protocol population.

f Gd-enhancing lesion or new T2 lesions.

CDMS, clinically definite multiple sclerosis; CI, confidence interval; DB, double-blind; GA, glatiramer acetate; Gd, gadolinium; IFNβ, interferon beta; NS, not significant; OL, open-label; PC, placebo-controlled; PG, parallel-group; R, randomized; RMS, relapsing forms of MS; SPMS, secondary progressive MS.

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  • 8. Vermersch P, Czlonkowska A, Grimaldi LM, et al. Teriflunomide versus subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis: a randomised, controlled phase 3 trial.Mult Scler.2014;20(6):705–716.
  • 9. Freedman M, Wolinsky J, Comi G, et al. Safety and Efficacy of Teriflunomide in Patients With Relapsing Multiple Sclerosis Treated With Interferon Beta. Paper presented at: 8th World Congress on Controversies in Neurology2014; Berlin, Germany.

In general, teriflunomide was well-tolerated and exhibited a favorable safety profile, including in Phase II studies when used as an adjunct therapy in combination with IFNβ or glatiramer acetate (Freedman, 2013, Garnock-Jones, 2013, and Sartori et al, 2014). A recent study that pooled results of the three major double-blind placebo controlled studies of teriflunomide, reported that 7 mg and 14 mg daily dosing regimens were associated with similar and manageable safety and tolerability profiles ( Leist et al., 2013 ). In over 2400 patients with cumulative treatment exposures amounting to over 1200 patient-years in each (7 mg or 14 mg) dosing cohort, the most commonly reported adverse events that were attributed to teriflunomide included gastrointestinal symptoms (principally nausea and diarrhea, typically mild to moderate and resolving by three months of treatment initiation), hair thinning, liver enzyme abnormalities (principally elevated alanine aminotransferase, ALT) and headache.

Rates of serious infections were low (< 2.5%) and no differences were seen across groups, including placebo. Adverse event survey identified 2 opportunistic infections in patients treated with teriflunomide 14 mg (gastrointestinal tuberculosis and hepatitis with cytomegalovirus (CMV) infection); none in patients treated with teriflunomide 7 mg; and 2 in placebo-treated patients (herpes zoster and hepatitis C with CMV infection). Up to approximately 15% decreases in circulating lymphocyte and neutrophil counts were observed while mean absolute counts remained within the normal range. Tumors (whether benign or malignant) were rarely seen (< 0.5%) across all groups, in all three studies. No hematopoietic tumors were reported ( Leist et al., 2013 ). Peripheral neuropathy was documented in a low frequency of patients treated with teriflunomide (7 mg, 1.2%; 14 mg, 1.9%) and in none of the placebo treated patients.

Rates of treatment discontinuation attributed to teriflunomide were overall relatively low (teriflunomide 7 mg 11.0%; teriflunomide 14 mg 13.6%, compared to placebo 6.9%). Many of these were protocol-required (such as ALT elevation of ≥ 3 ULN on two consecutive measures). There have been no unexpected adverse events attributed to teriflunomide in the extension phase studies, including the Phase II extension trial (ClinicalTrials.gov: NCT00228163) last reported with close to 9 years of follow-up for 147 patients ( Confavreux et al., 2012 ). In this relatively long-term (albeit relatively small) teriflunomide treatment cohort, 18.5% of patients taking 7 mg and 19.7% of patients taking 14 mg of teriflunomide discontinued due to treatment-emergent reasons. Most, again, were related to protocol mandated withdrawal due to increase liver enzymes.

Lessons from leflunomide in treatment of RA

The parent compound of teriflunomide is leflunomide (ARAVA), which has been approved for the treatment of rheumatoid arthritis (RA) where it is commonly used as a second line/add on therapy ( Keen et al., 2013 ). The considerable experience with leflunomide in RA has on one hand revealed some potential risks for this category of agents and, at the same time, has provided the MS community with overall reassuring insights from a sizable population exposed over > 2.3 million patient-years to an agent very similar to teriflunomide. While viewed as quite a safe agent in the context of RA, leflunomide treatment has nonetheless been associated with some serious adverse events including death, for example from liver toxicity and some increased risk of infection. These have mostly been in the context of multiple immune therapies and in a population of patients experiencing a range of additional medical co-morbidities that are likely to contribute to various risks ( Keen et al., 2013 ). Pregnancy outcomes observed with leflunomide from the OTIS studies, showed no difference in rates of fetal abnormalities in leflunomide (Arava)-treated RA patients vs RA untreated or healthy control groups. Nonetheless, the pregnancy category ‘X’ and the need for liver monitoring are both important and well-recognized issues with leflunomide that have carried over to teriflunomide considerations in MS.

Teriflunomide clinical considerations

Liver

A relatively common side effect of teriflunomide treatment is the transient and asymptomatic increase in blood levels of liver enzymes (principally ALT), though none of these were associated with increases in bilirubin levels, and no differences were observed in the occurrence rates of ALT increases above 3 × ULN, or in the incidence of serious hepatic complications, across groups ( Leist et al., 2013 ). Since a common protocol requirement in all studies required treatment discontinuation when ALT levels exceeded 3 × ULN on two consecutive occasions, little is known about the potential risks associated with persistent increases in ALT above 3 x ULN, and monitoring is recommended.

Hair thinning/loss

Compared to placebo (4.5%), hair thinning or loss occurred more frequently with teriflunomide (7 mg, 11.0%; 14 mg, 14.6%) treatment. Such hair thinning is thought to reflecttelogen effluvium(rapid evolution into the resting phase of the hair follicles), a process that is reversible and, indeed in patients resolved in approximately 85% of patients without treatment discontinuation.

Blood pressure

At week 108, pooled data indicated a small-magnitude (no more than 1.6 mm Hg) rise in diastolic, and up to 3 mm Hg in systolic blood pressure, in teriflunomide treated patients compared to those on placebo ( Leist et al., 2013 ). None of the blood pressure elevations led to therapy discontinuation.

Pregnancy

Teriflunomide carries a pregnancy category ‘X’, based on documented teratogenic potential of its parent compound, leflunomide, in animal models. Requirements for reliable contraception were implemented during the clinical trials and the same recommendation has extended into post-marketing use. Nonetheless, the teriflunomide clinical trial database (October 18, 2013 cutoff) identified 83 pregnancies in female patients, and 22 in partners of male patients (Kieseier et al, 2013 and Lu et al, 2014). Of these, outcomes were available from 70 pregnancies in women exposed to teriflunomide during gestation: there were 26 healthy newborns, 29 induced abortions, 13 spontaneous abortions and 1 ongoing pregnancies and one outcome unknown. Outcomes for 19 female partners of men exposed to the drug included 16 healthy newborns, 2 induced abortion, and 1 spontaneous abortion. None of the newborns had functional or structural defects and the spontaneous abortion rate of approximately 19% was not different from that expected in the general population (Kieseier et al, 2013 and Lu et al, 2014). While observations are reassuring, reliable contraception should still be used while on treatment with teriflunomide, and elimination should be accelerated (with cholestyramine or activated charcoal) when planning to conceive.

Approach to treatment with teriflunomide

Recommendations will vary with region. The following is considered appropriate:

  • Prior to treatment initiation
    • 1. Confirm a negative pregnancy test prior to treatment initiation in women of childbearing age; have an appropriate discussion with a male patient whose partner is, or may wish to become, pregnant.
    • 2. In some regions, screening for tuberculosis is advised.
    • 3. Obtain pre-treatment blood pressure check
    • 4. Obtain new or recent (within six months) blood test for liver enzymes and complete blood count
  • Following treatment initiation
    • 1. Obtain monthly blood test for first six months (liver enzymes) then every 6 months.
    • 2. Obtain additional testing if symptoms/signs of liver involvement (nausea, vomiting, abdominal pain, unusual fatigue, loss of appetite, jaundice).
    • 3. Monitor renal function and potassium levels in patients with symptoms of renal failure or elevated potassium levels
    • 4. Periodic monitoring of blood pressure
    • 5. Monitor for symptoms/signs of infection, peripheral neuropathy
    • 6. Identify pregnancy or concern over serious complication (liver injury, infection) that would warrant rapid elimination of drug (using cholestyramine or charcoal).

Pharmacokinetics, pharmacodynamics, and presumed therapeutic mode of action (MOA) of teriflunomide

Pharmacokinetics

Teriflunomide, taken at oral doses of either 7 or 14 mg, reaches steady state plasma concentrations after approximately three months of regular dosing and has a relatively long median half-life (t1/2) estimated between 18 and 19 days ( Wiese et al., 2013 ). It is highly (99%) protein bound, making it highly bioavailable, with a volume of distribution greater than 10 l. Teriflunomide undergoes extensive metabolism in the liver, with steps including hydrolysis, oxidation, N-acetylation and sulfate conjugation (but relatively little cytochrome P450 involvement). Most metabolites are excreted by the kidney, while unmodified drug exists via the biliary system. Considerable enterohepatic recycling involves reabsorption of teriflunomide in the small intestine and back to the liver via the portal circulation, which contributes to very slow elimination from the plasma (8 months on average, up to 2 years). However, rapid elimination of teriflunomide from the body can be readily achieved with agents that prevent reabsorption such as cholestyramine or activated charcoal ( Wiese et al., 2013 ).

Pharmacodynamics

Biochemically, teriflunomide and its parent compound leflunomide have a well-established capacity to limit de novo synthesis of pyrimidine, as specific, non-competitive and reversible inhibitors of dihydo-orotate dehydrogenase (DHODH), a mitochondrial enzyme expressed at high levels in proliferating cells including lymphocytes (Bruneau et al, 1998, Cherwinski et al, 1995, and Ruckemann et al, 1998). This inhibition of pyrimidine synthesis results in a cytostatic effect, which is particularly significant for rapid, antigen-induced proliferative expansion of lymphocytes ( Pearce, 2010 ). As a result, the putative contributions of activated effector T and B cells to MS disease activity ( Gold and Wolinsky, 2011 ), would be expected to be reduced. In contrast, cells not triggered to proliferate strongly, including resting immune cells; cells undergoing homeostatic proliferation ( Jameson, 2002 ), and gastrointestinal mucosal cells which express lower levels of DHODH, are able to meet their pyrimidine requirements through the salvage pathway ( Fairbanks et al., 1995 ), and are minimally affected by teriflunomide's inhibition of DHODH. De novo pyrimidine synthesis is involved in several other cellular functions, including phospholipid synthesis, protein and lipid glycosylation ( Herrmann et al., 2000 ).

Immune effects of Teriflunomide in vitro

A number of in vitro studies have demonstrated that teriflunomide can mediate cell-cycle arrest without inducing apoptotic cell death in activated human lymphocytes, including CD4 and CD8 T cells, as well as B cells (Bar-Or et al, 2014, Li et al, 2013, and Ringshausen et al, 2008). These in vitro effects of teriflunomide can be completely blocked by the addition of exogenous uridine, confirming that the drugs cytostatic effects are mediated via DHODH-dependent blockade of de novo pyrimidine synthesis ( Li et al., 2013 ). There is a suggestion that the anti-proliferative effects of teriflunomide on T cells are more evident when the T cells express T-cell receptors (TCR) with high affinity for the activating peptide antigen ( Posevitz et al., 2012 ). This may have consequences in the context of autoimmune disease, in which pathogenic T cells may exhibit abnormally high avidities to self-antigens within the target tissue ( Bielekova et al., 2004 ). It is conceivable that teriflunomide would then exhibit a selective cytostatic effect on disease-relevant autoreactive T-cells, while relatively sparing the lower avidity T cells which would remain capable of mounting normal immune responses. Teriflunomide may exert some DHODH-independent actions. For example, it has been shown in vitro to limit activation of integrins and decrease protein aggregation—both of which could limit interactions between antigen-presenting cells and T cells (Bar-Or et al, 2014, Fuentealba et al, 2012, and Zeyda et al, 2005). Additional DHODH-independent anti-inflammatory action of teriflunomide may include its observed in vitro ability to limit the secretion of pro-inflammatory molecules from immune cells, including IL-6, IL-8 and monocyte chemotactic protein-1 (MCP-1). One notes that some of these DHODH-independent effects of teriflunomide were observed with in vitro addition of rather high concentrations of the drug, such that it is not immediately clear how these findings translate into its in vivo effects.

In vivo effects of teriflunomide in animal models of CNS inflammation

Use of teriflunomide, both prophylactically and as treatment of established disease, has been shown to improve outcomes in a number of models of experimental autoimmune encephalomyelitis (EAE) where the benefits were attributed its immune modulatory properties (Dimitrova et al, 2002, Iglesias-Bregna et al, 2013, Korn et al, 2004, Merrill et al, 2009, and Ringheim et al, 2013). These studies included an adoptive transfer model in Lewis rats, in which activation of MBP-specific T cells in presence of teriflunomide prior to the adoptive transfer, resulted in less severe EAE outcomes (Dimitrova et al, 2002 and Korn et al, 2004). More recently, improved outcomes following teriflunomide treatment were also noted in the relapsing remitting Dark Agouti (DA) rat model of EAE ( Merrill et al., 2009 ). This benefit in DA rat EAE was associated with substantial reductions in numbers of infiltrating T cells, NK cells, macrophages and neutrophils ( Ringheim et al., 2013 ), and considerably lesser demyelination and axonal loss ( Merrill et al., 2009 ). At a functional level, electrophysiological (somatosensory-evoked potential magnetic stimulation) studies demonstrated that treating animals either prophylactically or therapeutically with teriflunomide preserved waveform amplitude and waveform initiation in the EAE animals (Iglesias-Bregna et al, 2013 and Merrill et al, 2009). Current thinking is that these beneficial effects on EAE pathologic and clinical outcomes reflect teriflunomide's effects on immune cell responses, rather than direct effects of teriflunomide on the CNS cells. Another animal model of CNS inflammation is the TMEV infection model, which initially causes a polioencephalomyelitis with neuronal loss, followed by a chronic period of inflammatory demyelination with oligodendrocyte apoptosis and axonal degeneration ( Tsunoda and Fujinami, 2010 ). Teriflunomide treatment was also beneficial in the TMEV model, resulting in decreased progression of neurological deficits ( Pachner and Li, 2013 ).

Insights into teriflunomide's MOA from clinical studies

Results of the teriflunomide clinical trial program demonstrated an anti-inflammatory effect of the drug as evidenced by decreased clinical and imaging measures of inflammatory disease activity in treated MS patients compared to placebo (Bar-Or et al, 2013a, Confavreux et al, 2012, Confavreux et al, 2014, Freedman et al, 2011, Freedman et al, 2012, Freedman et al, 2014, Kieseier and Wiendl, 2014, Miller et al, 2012, Miller et al, 2014, O'Connor et al, 2006, O'Connor et al, 2011, O'Connor et al, 2013, Vermersch et al, 2014, Wingerchuk and Carter, 2014, and Wolinsky et al, 2013). At the same time teriflunomide did not appear to functionally immune-suppress patients, as evidenced by the overall low incidence of infections and malignancies (no different from placebo-treated or IFNβ-treated patients) and the overall preserved ability of treated individuals to mount effective protective immune responses (Bar-Or et al, 2013a, Bar-Or et al, 2013b, and Singer et al, 2013). Pharmacodynamic assessments of teriflunomide's in vivo effects on circulating immune cell counts (in the combined Phase II and Phase III studies), demonstrated that treatment resulted in an average decrease in absolute leucocyte counts of approximately 15% ( Singer et al., 2013 ). These decreased leukocytes counts (which remained within the normal range), were observed over the first 6 months of treatment and levels remained stable with longer-term treatment. In spite of these decreases in leukocyte counts, the incidence of serious infections remained low in teriflunomide-treated patients, and did not differ significantly from the incidence in placebo-treated patients ( Singer et al., 2013 ). There was no increased signal for serious infections or malignancies in the long-term phase 2 and TEMSO extension studies (up to 8.5 years of teriflunomide treatment) ( O'Connor et al., 2011 ). Another aspect of protective host immune responses in the context of teriflunomide exposure has been assessed in vaccination studies, including immunizations with both recall and neoantigens (Bar-Or et al, 2013a and Bar-Or et al, 2013b). The first study assessed seasonal influenza (recall) vaccine responses in MS patients treated with either 7 mg or 14 mg of daily teriflunomide for at least 6 months. Vaccinated patients on stable treatment with IFNβ were studied as a reference group ( Bar-Or et al., 2013a ). Most patients had influenza antibodies detectable at baseline, as a reflection of pre-existing immunity. The ratios of post-vaccination to pre-vaccination anti-viral titers (post/pre) were > 2.5 for all treatment groups and for all viral strains (with the exception of the H1N1 strain in the teriflunomide 14 mg group). Protective antibody responses, defined as anti-viral titers ≥ 40 in at least 70% of the population ( European Agency for the Evaluation of Medical Products, 1997 ), were achieved following the influenza vaccination in at least 77% for all influenza strains, and in all treatment groups. The kinetics of induction of the anti-viral antibody responses were slower in the patients treated with teriflunomide. Thus, while teriflunomide treatment did impact immune responses to vaccination (both quantitatively and qualitatively), these effects did not compromise the capacity of patients to mount appropriate protective vaccine responses to the recall influenza vaccination ( Bar-Or et al., 2013b ). To assess the impact of teriflunomide exposure on the ability to mount vaccine responses to neoantigen, healthy subjects, with no prior exposure to rabies or rabies vaccine, received either placebo or teriflunomide for 1 month and were then vaccinated with the rabies vaccine ( Bar-Or et al., 2013b ). Teriflunomide treatment was associated with a slightly lower mean anti-rabies antibody response compared to responses in placebo-treated subjects; however, adequate seroprotection to the rabies neoantigen was achieved in all subjects ( Bar-Or et al., 2013b ).

Summary

Teriflunomide (Aubagio®) is a once-a-day oral therapy, recently approved for the treatment of relapsing forms of MS based on demonstration of efficacy on both clinical and imaging endpoints in the phase III program, together with overall favorable safety and tolerability profiles, supported by results of both the core as well as longer-term extension studies. While its therapeutic mode of action is not fully elucidated, emerging studies suggest that it may have a number of beneficial immune modulatory effects. These likely include its ability to specifically and reversibly inhibit the mitochondrial enzyme DHODH, required for de novo pyrimidine biosynthesis particularly in activated lymphocytes. As a result, teriflunomide limits proliferation of activated T cells and B cells, presumably reducing their ability to participate in pro-inflammatory pathogenic responses targeting the CNS of patients with MS. A growing body of in vitro, pre-clinical (animal model) and in vivo results in human studies, support the concept that teriflunomide's immune effects are selective and overall achieve a favorable balance between efficacy (limiting new inflammatory disease activity) and safety (preserving host protective immune responses). Given the selectivity of its effects on the immune system, teriflunomide represents a valuable addition to the list of approved therapies available to treat patients with MS. As such, teriflunomide with its once daily oral dosing offers certain advantages over first-line injectable DMTs and is a welcome addition to the growing therapeutic arsenal targeting relapsing disease activity in patients with multiple sclerosis.

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Footnotes

Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, 3801 University Street, # 111, Montreal, Quebec, Canada, H3A 2B4

Experimental Therapeutics Program, Montreal Neurological Institute, McGill University, 3801 University Street, # 111, Montreal, Quebec, Canada, H3A 2B4

Clinical Research Unit, Montreal Neurological Institute, McGill University, 3801 University Street, # 111, Montreal, Quebec, Canada, H3A 2B4

lowast Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, 3801 University Street, # 111, Montreal, Quebec, Canada, H3A 2B4.