An update of teriflunomide for treatment of multiple sclerosis

Introduction

Most of the available disease-modifying agents (DMAs) approved for use for the treatment of multiple sclerosis (MS) are administered parenterally, making the burden of medication administration substantial for patients. In recent years, a number of oral agents have emerged as potential therapeutic options in MS, with beneficial effects demonstrated in large, multicenter, phase III clinical trials.1 Teriflunomide (Aubagio^®) is a novel oral drug that has shown promise with respect to clinical efficacy and safety in relapsing MS patients, and was recently approved by the Food and Drug Administration (FDA) of the United States of America for treatment of relapsing forms of MS. This review will clarify the role of teriflunomide in the context of current and emerging MS treatment options by summarizing relevant points on the use of teriflunomide in MS, with a discussion of teriflunomide’s development, pharmacologic properties, animal studies and clinical trials, and safety and tolerability.

Development of teriflunomide

Teriflunomide is the principal active metabolite of leflunomide, which has been licensed for use in the treatment of rheumatoid arthritis (RA) for over a decade (Figure 1).2 Leflunomide was discovered in the 1980s during a chemical compound-screening process intended to identify agricultural pesticides, and was inadvertently found to have both anti-inflammatory and immunosuppressive properties,3 and was thus developed for use in RA. Due to its efficacy, safety, and tolerability in RA, leflunomide was later tested in animal models of other inflammatory disorders, including experimental autoimmune encephalitis,4 the animal model of MS. Upon oral ingestion, leflunomide is rapidly converted into its primary active metabolite, teriflunomide. Since teriflunomide is able to avoid the first-pass metabolism that leflunomide undergoes, it has become the focus of development in MS patients.

Clinical pharmacology: mechanism of action of teriflunomide

The precise mechanisms by which teriflunomide exerts immunomodulatory effects in MS are incompletely understood. Teriflunomide primarily acts as an inhibitor of dihydroorotate dehydrogenase (DHODH), a key mitochondrial enzyme involved in the de novo synthesis of pyrimidines in rapidly proliferating cells. By reducing the activity of high-avidity proliferating T lymphocytes and B lymphocytes, teriflunomide likely attenuates the inflammatory response to autoantigens in MS.5 Of note, DHODH blockade does not affect resting or homeostatically proliferating hematopoietic cell lines, as pyrimidine pools in these cells can be generated through an alternate “salvage pathway,” which is independent of the DHODH.6–9 As a result, basic homeostatic functions of resting and slowly dividing cells appear to be preserved, and lymphocytes remain available for immune surveillance. Thus, teriflunomide can be considered a cytostatic rather than a cytotoxic drug to leukocytes. In addition to DNA and RNA synthesis, pyrimidines are involved in a myriad of cellular functions, including protein and lipid glycosylation, phospholipid synthesis,10 and DNA strand repair,11 together which lead to a variety of downstream immunomodulatory effects (Figure 2).

Teriflunomide appears to have additional effects independent of DHODH inhibition, which likely account for a portion of its observed beneficial effects in MS. In vitro studies have demonstrated that in the presence of teriflunomide, exogenous reconstitution of pyrimidines will restore immune-cell proliferation,12 but other functions such as cytokine production, expression of cell-surface molecules, and cellular migration remain impaired. These observations suggest that teriflunomide has immunological effects outside of its ability to inhibit pyrimidine synthesis in rapidly proliferating cells.4,13

One identified DHODH-independent effect of teriflunomide is the inhibition of protein tyrosine kinases, which can result in a variety of downstream effects, including: a decrease in T-cell proliferation, diminished production of proinflammatory cytokines such as interferon (IFN)-γ and interleukin 2, and inhibition of protein complexes such as nuclear factor kappa B.14–20 Another identified DHODH-independent effect of teriflunomide is its ability to inhibit the activity and expression of cyclooxygenase-2,21 and to reduce inducible nitric oxide synthase in astrocytes.20,22 Furthermore, there is evidence suggesting that teriflunomide modulates T-cell function by altering integrin function and intracellular calcium signaling,13,23,24 shifting the immune cytokine profile towards an anti-inflammatory T-helper 2 state,4,25 and by diminishing T-cell activation via antigen-presenting cells.23,26 Finally, teriflunomide may also affect components of the innate immune system by altering the function of adhesion molecules in neutrophils and macrophages,27–29 and by causing increased secretion of interleukin 10 by macrophages and microglia.4

Finally, a recent study has demonstrated that teriflunomide has the ability to inhibit intracellular polyglutamine protein aggregation in vitro, independently of its effects on pyrimidine biosynthesis.30 Abnormal protein aggregation is a common pathological mechanism in a spectrum of neurodegenerative disorders, including Parkinson’s disease and Huntington’s disease. If confirmed, this suggests that teriflunomide may be of clinical utility in a broad spectrum of neurodegenerative neurological disorders.

Although many of these additional postulated effects of teriflunomide have been demonstrated in vitro and in animal models, the extent to which these mechanisms play a role in MS is unclear. Average steady-state maximum plasma concentrations (C_max) of teriflunomide achieved with doses used in clinical trials are 168 μM (14 mg) and 72 μM (7 mg).31 Concentrations of teriflunomide in vitro necessary to achieve its DHODH-independent mechanisms such as protein tyrosine kinase inhibition (50–100 μM )12,31 and cyclooxygenase-2 inhibition (100–200 μM)21,31 are many orders of magnitude larger than what is necessary to achieve DHODH inhibition (1250 nM),8 making it entirely possible that these mechanisms may be of limited relevance in teriflunomide’s clinical effects in MS.8,10

Pharmacokinetics

Food intake and hepatic impairment do not affect teriflunomide’s pharmacokinetics, although concomitant food ingestion does impair the initial absorption. Teriflunomide’s oral bioavailability is ~100%, with peak plasma levels observed within 1–2 hours of ingestion. Teriflunomide is >99% protein-bound in plasma and demonstrates linear pharmacokinetics at a dose range of 7–100 mg/day, with a mean plasma half-life ranging between 10 and 12 days.32 C_max of teriflunomide is 45.3 μg/mL (14 mg) and 19.5 μg/mL (7 mg), and there is a slow approach to steady state (3–3.25 months).31 Biliary and minor renal mechanisms contribute to drug clearance, thus washout procedures using cholestyramine or activated charcoal can facilitate clearance of teriflunomide.32,33

Use of teriflunomide in animal models of multiple sclerosis

Teriflunomide has demonstrated beneficial effects in two independent animal models of demyelinating disease. In the dark agouti rat model of experimental autoimmune encephalitis (EAE), which is a chronic animal model of demyelinating disease more reminiscent of relapsing MS in comparison to adoptive-transfer EAE,34–36 teriflunomide administration resulted in clinical, histopathological, and electrophysiological evidence of efficacy both as a prophylactic and therapeutic agent. From a clinical standpoint, teriflunomide delayed the onset of disease and reduced the maximal disability acquired in affected rats in comparison to controls. In animals already displaying clinical signs of disease, or in animals in disease remission, therapeutic doses of teriflunomide reduced maximal cumulative disability in comparison to controls. Corresponding pathological assessments of the rat spinal cords showed evidence of decreased inflammation, demyelination, and axonal loss with teriflunomide administration, which supported the observed clinical findings. From an electrophysiologic standpoint, in animals treated therapeutically with teriflunomide, somatosensory-evoked potentials demonstrated preserved wave amplitudes and wave latencies, both findings which support the clinical observations.37

Similarly, in the female Lewis rat model of EAE, which is another animal model of demyelinating disease, teriflunomide administration resulted in beneficial prophylactic and therapeutic clinical effects, with a delay in disease onset and symptom severity.38 Teriflunomide’s demonstrated beneficial clinical effects in two independent animal models provides strong evidence supporting the efficacy of teriflunomide in animals, thereby supporting the experimental use of this agent in human clinical studies.

Phase II clinical trials of teriflunomide in multiple sclerosis

Phase III clinical trials of teriflunomide in multiple sclerosis

Safety and tolerability

Teriflunomide is generally a well-tolerated drug, with predominately mild to moderate treatment-emergent adverse events (TEAEs), and only rare serious adverse events (SAEs). The available safety and tolerability data on teriflunomide have been derived from the phase II clinical trial, its open-label extension, and the subsequent phase III clinical trials (TEMSO, TOWER).39,40,46,48

In the phase II clinical trial, there was a similar incidence of TEAEs across the placebo and teriflunomide treatment arms. TEAEs that were more commonly reported in teriflunomide-treated patients included nasopharyngitis, alopecia, nausea, alanine aminotransferase (ALT) increase, paresthesia, back and limb pain, diarrhea, and arthralgia. Observed SAEs included elevated liver-function tests, hepatic dysfunction, neutropenia, rhabdomyolysis, and trigeminal neuralgia, and the incidence of these events was similar across the placebo and treatment arms. There was no significant difference in numbers of patients with significantly abnormal laboratory tests across treatment arms, but there was a higher frequency of TEAEs leading to study withdrawal in the high-dose teriflunomide treatment arm.39

Subsequently, the open-label extension (with up to 8.5 years’ follow-up) of the phase II clinical trial confirmed the safety and tolerability profile observed in the double-blind phase of the study. The incidence of TEAEs was similar across teriflunomide treatment arms, with the exception of oral herpes infection, which was more common in the high-dose teriflunomide treatment arm. Furthermore, the number of SAEs was similar across both doses of teriflunomide. Asymptomatic ALT increases (≤3 × upper limit of normal [ULN]) were common (7 mg, 64.2%; 14 mg, 62.1%) and increases > 3 × ULN were similar across treatment groups (7 mg, 12.3%; 14 mg, 12.1%). In individuals with significant increases, laboratory value normalization occurred within 2 months of treatment discontinuation in the majority of cases. There was a higher incidence of leukopenia observed in the 14 mg teriflunomide treatment arm (3.7% and 18.2% seen in the 7 mg and 14 mg groups, respectively), but the magnitude of the decrease in white blood cell count was low and did not lead to treatment discontinuation in any of the cases.40

In the reported open-label extension of the phase II clinical trial,40 there have been no reports of serious opportunistic infections or hypersensitivity reactions with teriflunomide use. In addition, the incidence of malignancy was similar to population-based estimates, with no pattern suggestive of immunosuppression-related malignancy. There was a single death due to a sudden cardiac disorder in the reported open-label extension;40 however, an extensive safety evaluation concluded that it is difficult to attribute this death solely to teriflunomide, and that concomitant medical conditions and medications are likely to have contributed.40

Reassuringly, the safety and tolerability of teriflunomide in TEMSO was similar to what was observed in the phase II clinical trial and open-label extension, without the emergence of any new safety concerns and no reported deaths. Specifically, the incidence of AEs (87.5%, 89.1%, and 90.8%, in placebo, 7 mg teriflunomide, and 14 mg teriflunomide, respectively) and SAEs (12.8%, 14.1%, and 15.9% in placebo, low-dose teriflunomide, and high-dose teriflunomide, respectively), were similar across treatment arms, as were AEs leading to study discontinuation (8.1%, 9.8%, and 10.9% in placebo, 7 mg teriflunomide, and 14 mg teriflunomide, respectively). AEs observed more frequently with teriflunomide treatment and associated with a dose effect included nausea, diarrhea, hair thinning or decreased hair density, and elevated ALT levels (seen in 35.9% of placebo, 54.0% of teriflunomide 7 mg, and 57.3% of teriflunomide 14 mg patients). Reductions in neutrophil and lymphocyte counts were small in magnitude, and tended to stabilize within 3 months. In rare individuals with moderate neutropenia (n = 3), continued treatment resulted in spontaneous resolution in two patients, while in one patient there was resolution with discontinuation of teriflunomide. There were no deaths or serious opportunistic infections observed.46

Similarly, in TOWER, the total number of AEs, SAEs, and AEs leading to discontinuation were similar across the placebo, teriflunomide 7 mg, and 14 mg treatment arms. AEs observed in TOWER were consistent with those reported in previous clinical trials with teriflunomide in MS, and the most common AEs reported more frequently in the teriflunomide treatment groups were headache, increase in ALT, hair thinning or alopecia, diarrhea, nausea, and neutropenia. There was no indication of increased infection in the teriflunomide treatment arms. There were four deaths reported in TOWER: three in the teriflunomide treatment arms and one in the placebo arm. The three deaths in the teriflunomide arms were due to suicide, a motor vehicle accident, and sepsis, while the death in the placebo arm was due to respiratory infection.48

Animal studies have demonstrated the teratogenic potential of leflunomide.51,52 Animal studies of teriflunomide have demonstrated embryotoxicity and teratogenicity;31 however, the teratogenic risk of teriflunomide in humans has not been well characterized due to limited experience. In light of leflunomide’s known teratogenicity in animals, strict contraception is recommended for all females of reproductive age taking this drug, and males are cautioned not to father a child while on therapy, as teriflunomide may be transmitted in semen and the degree of transvaginal absorption is not well characterized.

In the teriflunomide clinical trials, women who became pregnant were required to undergo a cholestyramine or activated charcoal-based washout procedure after treatment discontinuation, and it was necessary to confirm that the plasma level was <0.02 g/L, which is thought to be a level representing minimal risk in pregnancy. Without undergoing the washout procedure, it can take up to 2 years to achieve systemic clearance of teriflunomide that is at an acceptable level.39

In the phase II clinical trial, there were six pregnancies documented. Four patients chose to terminate the pregnancy, but two underwent the washout procedure as soon as they became aware of the pregnancy, and in both cases subsequently delivered healthy infants with no structural deficits or other health concerns.39 Similarly, in the phase III clinical trial, there were eleven pregnancies reported, with four spontaneous abortions and six induced abortions. One patient in the 14 mg teriflunomide treatment arm had been on teriflunomide for 31 days of her pregnancy, underwent the washout procedure, and delivered a healthy child with no significant health concerns.46

A recent cohort study evaluated the safety of leflunomide in 64 RA patients, and did not find an increase in structural AEs in infants.53 Another study evaluating 45 patients exposed to leflunomide during pregnancy or preconception resulted in two children with structural anomalies; however, there was a potential alternate etiology identified for at least some of the observed defects.54 A recent analysis of 65 pregnancies reported in all clinical trials of teriflunomide to date found no structural or functional deficits in any newborns with prenatal teriflunomide exposure following elimination. Furthermore, the proportion of spontaneous abortions was within population-based norms.55 Although these studies are somewhat reassuring for women who become inadvertently pregnant while on leflunomide or teriflunomide, at the present time, in the absence of any definitive clinical data, teriflunomide’s teratogenic potential remains a significant concern. Thus, for the time being, individuals taking teriflunomide should practice strict contraception.

The availability of long-term safety data on leflunomide can further supplement the safety and tolerability profile of teriflunomide. Overall, postmarketing surveillance of leflunomide suggests that its safety profile is acceptable. Nausea, diarrhea, and alopecia are the most commonly reported AEs, but these events rarely lead to medication discontinuation. However, leflunomide does have associated rare SAEs, including hepatic toxicity, which is uncommonly seen. In addition, rarer SAEs include peripheral neuropathy, hypertension, pneumonitis, and cytopenia.56 There have been two cases of progressive multifocal leukoencephalopathy reported in the context of approximately 2.1 million years of leflunomide use. One of these cases was reported in a patient who had previously been on five other immunosuppressants: azathioprine, chloroquine, danazol, cyclosporin A, and methotrexate.57 The second case was a patient who had previously been on azathioprine.58

Although teriflunomide’s safety profile based on the existing clinical trials has been relatively benign, given the rare SAEs seen with long-term safety data available from leflunomide, a high degree of vigilance should be practiced when monitoring patients on this novel DMA.57

Current FDA safety-monitoring guidelines for teriflunomide recommend obtaining a baseline complete blood count and liver function tests (transaminases and bilirubin) within 6 months before initiation of teriflunomide, and monitoring monthly liver-function tests for 6 months after initiation of therapy. Subsequent liver-function testing should be performed at the discretion of the prescribing physician. Complete blood count should be monitored if there are any signs or symptoms of hematologic toxicity. A baseline blood pressure should also be obtained, and blood pressure should be monitored periodically thereafter. Prior to teriflunomide initiation, the FDA also recommends that patients should be screened for latent tuberculosis infection with a tuberculin skin test; positive cases should be treated according to the standard of care prior to initiation of teriflunomide (Figure 3).

Conclusion

Teriflunomide shows promise as a relatively safe and efficacious oral DMA in the treatment of relapsing MS, both as monotherapy or as an add-on agent. The convenience of oral administration makes teriflunomide an attractive agent to add to the available treatment armamentarium of relapsing MS. Furthermore, existing experience with a closely related drug, leflunomide, gives teriflunomide the added benefit of indirect long-term safety data, which is of considerable benefit, since long-term safety is ultimately one of the most important factors that determine the clinical utility of a drug in the treatment of MS.

Although only head-to-head clinical trials with other existing therapies can provide more definitive evidence of teriflunomide’s relative efficacy to other DMAs, based on currently available data, teriflunomide appears likely to have similar efficacy to existing first-line treatments (IFN-β and GA) as monotherapy, but has the added convenience of oral administration. In addition, teriflunomide appears to demonstrate efficacy as an add-on agent to first-line DMAs. Thus, the use of teriflunomide in the “real world” will likely be as a first-line monotherapy agent. Theoretically, teriflunomide might be considered for use as an add-on therapy in patients with suboptimal responses to first-line injectable DMAs who are reluctant or unable to use other approved DMAs. However, cost would be a significant issue in this setting, and would greatly reduce the probability of this happening in day-to-day practice.

Results from ongoing large-scale phase III clinical trials will provide additional information on the efficacy and tolerability of teriflunomide. Possible concerns requiring further clarification include teriflunomide’s potential teratogenicity and unknown potential for malignancy or serious infectious complications. In addition, the long washout period of teriflunomide may have implications for the use of other immunosuppressive agents in individuals with breakthrough disease on this drug, although rapid-elimination procedures may mitigate this concern. Most importantly, as with any novel pharmacological agent, postmarketing surveillance will be essential in more definitively characterizing the long-term safety and efficacy of teriflunomide in the treatment of MS in the real world.