Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Sanofi Winthrop Industrie, 82 avenue Raspail, 94250 Gentilly, France
Pharmacotherapeutic group: Immunosuppressants, Selective immunosuppressants
ATC Code: L04AA31
Teriflunomide is an immunomodulatory agent with anti-inflammatory properties that selectively and reversibly inhibits the mitochondrial enzyme dihydroorotate dehydrogenase (DHO-DH), which functionally connects with the respiratory chain. As a consequence of the inhibition, teriflunomide generally reduces the proliferation of rapidly dividing cells that depend on de novo synthesis of pyrimidine to expand. The exact mechanism by which teriflunomide exerts its therapeutic effect in MS is not fully understood, but this is mediated by a reduced number of lymphocytes.
Effects on immune cell numbers in the blood: In the placebo-controlled studies, teriflunomide 14 mg once a day led to a mild mean reduction in lymphocyte count, of less than 0.3 × 109/l, which occurred over the first 3 months of treatment and levels were maintained until the end of the treatment.
In a placebo-controlled thorough QT study performed in healthy subjects, teriflunomide at mean steady-state concentrations did not show any potential for prolonging the QTcF interval compared with placebo: the largest time matched mean difference between teriflunomide and placebo was 3.45 ms with the upper bound of the 90% CI being 6.45 ms.
In the placebo-controlled studies, mean decreases in serum uric acid at a range of 20 to 30% were observed in patients treated with teriflunomide compared to placebo. Mean decrease in serum phosphorus was around 10% in the teriflunomide group compared to placebo. These effects are considered to be related to increase in renal tubular excretion and not related to changes in glomerular functions.
The efficacy of AUBAGIO was demonstrated in two placebo-controlled studies, the TEMSO and the TOWER study, that evaluated once daily doses of teriflunomide 7 mg and 14 mg in adult patients with RMS.
A total of 1,088 patients with RMS were randomised in TEMSO to receive 7 mg (n=366) or 14 mg (n=359) of teriflunomide or placebo (n=363) for 108 weeks duration. All patients had a definite diagnosis of MS (based on McDonald criteria (2001)), exhibited a relapsing clinical course, with or without progression, and experienced at least 1 relapse over the year preceding the trial or at least 2 relapses over the 2 years preceding the trial. At entry, patients had an Expanded Disability Status Scale (EDSS) score ≤5.5.
The mean age of the study population was 37.9 years. The majority of patients had relapsing–remitting multiple sclerosis (91.5%), but a subgroup of patients had secondary progressive (4.7%) or progressive relapsing multiple sclerosis (3.9%). The mean number of relapses within the year before study inclusion was 1.4 with 36.2% of patients having gadolinium-enhancing lesions at baseline. The median EDSS score at baseline was 2.50; 249 patients (22.9%) had an EDSS score >3.5 at baseline. The mean duration of disease, since first symptoms, was 8.7 years. A majority of patients (73%) had not received disease-modifying therapy during the 2 years before study entry. The study results are shown in Table 1.
Long term follow-up results from TEMSO long term extension safety study (overall median treatment duration approximately 5 years, maximum treatment duration approximately 8.5 years) did not present any new or unexpected safety findings.
A total of 1,169 patients with RMS were randomised in TOWER to receive 7 mg (n=408) or 14 mg (n=372) of teriflunomide or placebo (n=389) for a variable treatment duration ending at 48 weeks after last patient randomised. All patients had a definite diagnosis of MS (based on McDonald criteria (2005)), exhibited a relapsing clinical course, with or without progression, and experienced at least 1 relapse over the year preceding the trial or at least 2 relapses over the 2 years preceding the trial. At entry, patients had an Expanded Disability Status Scale (EDSS) score ≤5.5.
The mean age of the study population was 37.9 years. The majority of patients had relapsing–remitting multiple sclerosis (97.5%), but a subgroup of patients had secondary progressive (0.8%) or progressive relapsing multiple sclerosis (1.7%). The mean number of relapses within the year before study inclusion was 1.4. Gadolinium-enhancing lesions at baseline: no data. The median EDSS score at baseline was 2.50; 298 patients (25.5%) had an EDSS score ›3.5 at baseline. The mean duration of disease, since first symptoms, was 8.0 years. A majority of patients (67.2%) had not received diseasemodifying therapy during the 2 years before study entry. The study results are shown in Table 1.
Table 1. Main results (for the approved dose, ITT population):
| TEMSO-study | TOWER-study | |||
|---|---|---|---|---|
| Teriflunomide 14 mg | Placebo | Teriflunomide 14 mg | Placebo | |
| N | 358 | 363 | 370 | 388 |
| Clinical Outcomes | ||||
| Annualised relapse rate | 0.37 | 0.54 | 0.32 | 0.50 |
| Risk difference (CI95%) | -0.17 (-0.26, -0.08)*** | -0.18 (-0.27, -0.09)**** | ||
| Relapse-free week 108 | 56.5% | 45.6% | 57.1% | 46.8% |
| Hazard ratio (CI95%) | 0.72, (0.58, 0.89)** | 0.63, (0.50, 0.79)**** | ||
| 3-month Sustained Disability Progression week 108 | 20.2% | 27.3% | 15.8% | 19.7% |
| Hazard ratio (CI95%) | 0.70 (0.51, 0.97)* | 0.68 (0.47, 1.00)* | ||
| 6-month Sustained Disability Progression week 108 | 13.8% | 18.7% | 11.7% | 11.9% |
| Hazard ratio (CI95%) | 0.75 (0.50, 1.11) | 0.84 (0.53, 1.33) | ||
| MRI endpoints | Not measured | |||
| Change in BOD week 1081 | 0.72 | 2.21 | ||
| Change relative to placebo | 67%*** | |||
| Mean Number of Gd- enhancing lesions at week 108 | 0.38 | 1.18 | ||
| Change relative to placebo (CI95%) | -0.80 (-1.20, -0.39)**** | |||
| Number of unique active lesions/scan | 0.75 | 2.46 | ||
| Change relative to placebo (CI95%) | 69%, (59%; 77%)**** | |||
**** p<0.0001 ***p<0.001 **p<0.01 *p<0.05 compared to placebo
1 BOD: burden of disease: total lesion volume (T2 and T1 hypointense) in ml
Efficacy in patients with high disease activity:
A consistent treatment effect on relapses and time to 3-month sustained disability progression in a subgroup of patients in TEMSO (n=127) with high disease activity was observed. Due to the design of the study, high disease activity was defined as 2 or more relapses in one year, and with one or more Gd-enhancing lesion on brain MRI. No similar subgroup analysis was performed in TOWER as no MRI data were obtained.
No data are available in patients who have failed to respond to a full and adequate course (normally at least one year of treatment) of beta-interferon, having had at least 1 relapse in the previous year while on therapy, and at least 9 T2-hyperintense lesions in cranial MRI or at least 1 Gd-enhancing lesion, or patients having an unchanged or increased relapse rate in the prior year as compared to the previous 2 years.
TOPIC was a double-blind, placebo-controlled study that evaluated once daily doses of teriflunomide 7 mg and 14 mg for up to 108 weeks in patients with first clinical demyelinating event (mean age 32.1 years). The primary endpoint was time to a second clinical episode (relapse). A total of 618 patients were randomised to receive 7 mg (n=205) or 14 mg (n=216) of teriflunomide or placebo (n=197). The risk of a second clinical attack over 2 years was 35.9% in the placebo group and 24.0% in the teriflunomide 14 mg treatment group (hazard ratio: 0.57, 95% confidence interval: 0.38 to 0.87, p=0.0087). The results from the TOPIC study confirmed the efficacy of teriflunomide in RRMS (including early RRMS with first clinical demyelinating event and MRI lesions disseminated in time and space).
Teriflunomide effectiveness was compared to that of a subcutaneous interferon beta-1a (at the recommended dose of 44 µg three times a week) in 324 randomised patients in a study (TENERE) with minimum treatment duration of 48 weeks (maximum 114 weeks). The risk of failure (confirmed relapse or permanent treatment discontinuation whichever came first) was the primary endpoint. The number of patients with permanent treatment discontinuation in the teriflunomide 14 mg group was 22 out of 111 (19.8%), the reasons being adverse events (10.8%), lack of efficacy (3.6%), other reason (4.5%) and lost to follow-up (0.9%). The number of patients with permanent treatment discontinuation in the subcutaneous interferon beta-1a group was 30 out of 104 (28 .8%), the reasons being adverse events (21.2%), lack of efficacy (1.9%), other reason (4.8%) and poor compliance to protocol (1%). Teriflunomide 14 mg/day was not superior to interferon beta-1a on the primary endpoint: the estimated percentage of patients with treatment failure at 96 weeks using the Kaplan-Meier method was 41.1% versus 44.4% (teriflunomide 14 mg versus interferon beta-1a group, p=0.595).
Study EFC11759/TERIKIDS was an international double-blind, placebo-controlled study in paediatric patients aged 10 to 17 years with relapsing-remitting MS that evaluated once daily doses of teriflunomide (adjusted to reach an exposure equivalent to the dose of 14 mg in adults) for up to 96 weeks followed by an open-label extension. All patients had experienced at least 1 relapse over 1 year or at least 2 relapses over 2 years preceding the study. Neurological evaluations were performed at screening and every 24 weeks until the completion, and at unscheduled visits for suspected relapse. Patients with a clinical relapse or high MRI activity of at least 5 new or enlarging T2 lesions on 2 consecutive scans were switched prior to 96 weeks to the open-label extension to ensure active treatment. The primary endpoint was time to first clinical relapse after randomisation. Time to first confirmed clinical relapse or high MRI activity, whichever came first, was pre-defined as a sensitivity analysis because it includes both clinical and MRI conditions qualifying for switching into the open-label period.
A total of 166 patients were randomised at a 2:1 ratio to receive teriflunomide (n=109) or placebo (n=57). At entry, study patients had an EDSS score ≤5.5; the mean age was 14.6 years; the mean weight was 58.1 kg; the mean disease duration since diagnosis was 1.4 years; and the mean T1 Gdenhancing lesions per MRI scan was 3.9 lesions at baseline. All patients had relapsing remitting MS with the median EDSS score of 1.5 at baseline. The mean treatment time was 362 days on placebo and 488 days on teriflunomide. Switching from the double-blind period to open-label treatment due to high MRI activity was more frequent than anticipated, and more frequent and earlier in the placebo group than in the teriflunomide group (26% on placebo, 13% on teriflunomide).
Teriflunomide reduced the risk of clinical relapse by 34% relative to placebo, without reaching statistical significance (p=0.29) (Table 2). In the pre-defined sensitivity analysis, teriflunomide achieved a statistically significant reduction in the combined risk of clinical relapse or high MRI activity by 43% relative to placebo (p=0.04) (Table 2).
Teriflunomide significantly reduced the number of new and enlarging T2 lesions per scan by 55% (p=0.0006) (post-hoc analysis also adjusted for baseline T2 counts: 34%, p=0.0446), and the number of Gadolinium-enhancing T1 lesions per scan by 75% (p<0.0001) (Table 2).
Table 2. Clinical and MRI results of EFC11759/TERIKIDS:
| EFC11759 ITT population | Teriflunomide (N=109) | Placebo (N=57) |
|---|---|---|
| Clinical endpoints | ||
| Time to first confirmed clinical relapse, Probability (95%CI) of confirmed relapse at Week 96 Probability (95%CI) of confirmed relapse at Week 48 | 0.39 (0.29, 0.48) 0.30 (0.21, 0.39) | 0.53 (0.36, 0.68) 0.39 (0.30, 0.52) |
| Hazard Ratio (95% CI) | 0.66 (0.39, 1.11)^ | |
| Time to first confirmed clinical relapse or high MRI activity, Probability (95%CI) of confirmed relapse or high MRI activity at Week 96 Probability (95%CI) of confirmed relapse or high MRI activity at Week 48 | 0.51 (0.41, 0.60) 0.38 (0.29, 0.47) | 0.72 (0.58, 0.82) 0.56 (0.42, 0.68) |
| Hazard Ratio (95% CI) | 0.57 (0.37, 0.87)* | |
| Key MRI endpoints | ||
| Adjusted number of new or enlarged T2 lesions, Estimate (95% CI) Estimate (95% CI), post-hoc analysis also adjusted for baseline T2 counts | 4.74 (2.12, 10.57) 3.57 (1.97, 6.46) | 10.52 (4.71, 23.50) 5.37 (2.84, 10.16) |
| Relative risk (95% CI) Relative risk (95% CI), post-hoc analysis also adjusted for baseline T2 counts | 0.45 (0.29, 0.71)** 0.67 (0.45, 0.99)* | |
| Adjusted number of T1 Gd-enhancing lesions, Estimate (95% CI) | 1.90 (0.66, 5.49) | 7.51 (2.48, 22.70) |
| Relative risk (95% CI) | 0.25 (0.13, 0.51)*** | |
^ p≥0.05 compared to placebo, *p<0.05, **p<0.001, ***p<0.0001
Probability was based on Kaplan-Meier estimator and Week 96 was the end of study treatment (EOT).
The European Medicines Agency has waived the obligation to submit the results of studies with AUBAGIO in children from birth to less than 10 years in treatment of multiple sclerosis (see section 4.2 for information on paediatric use).
Median time to reach maximum plasma concentrations occurs between 1 to 4 hours post-dose following repeated oral administration of teriflunomide, with high bioavailability (approximately 100%).
Food does not have a clinically relevant effect on teriflunomide pharmacokinetics.
From the mean predicted pharmacokinetic parameters calculated from the population pharmacokinetic (PopPK) analysis using data from healthy volunteers and MS patients, there is a slow approach to steady- state concentration (i.e. approximately 100 days (3.5 months) to attain 95% of steady-state concentrations) and the estimated AUC accumulation ratio is approximately 34-fold.
Teriflunomide is extensively bound to plasma protein (>99%), probably albumin and is mainly distributed in plasma. The volume of distribution is 11 l after a single intravenous (IV) administration. However, this is most likely an underestimation since extensive organ distribution was observed in rats.
Teriflunomide is moderately metabolised and is the only component detected in plasma. The primary biotransformation pathway for teriflunomide is hydrolysis with oxidation being a minor pathway. Secondary pathways involve oxidation, N-acetylation and sulfate conjugation.
Teriflunomide is excreted in the gastrointestinal tract mainly through the bile as unchanged active substance and most likely by direct secretion. Teriflunomide is a substrate of the efflux transporter BCRP, which could be involved in direct secretion. Over 21 days, 60.1% of the administered dose is excreted via faeces (37.5%) and urine (22.6%). After the rapid elimination procedure with cholestyramine, an additional 23.1% was recovered (mostly in faeces). Based on individual prediction of pharmacokinetic parameters using the PopPK model of teriflunomide in healthy volunteers and MS patients, median t1/2z was approximately 19 days after repeated doses of 14 mg. After a single intravenous administration, the total body clearance of teriflunomide is 30.5 ml/h.
The elimination of teriflunomide from the circulation can be accelerated by administration of cholestyramine or activated charcoal, presumably by interrupting the reabsorption processes at the intestinal level. Teriflunomide concentrations measured during an 11-day procedure to accelerate teriflunomide elimination with either 8 g cholestyramine three times a day, 4 g cholestyramine three times a day or 50 g activated charcoal twice a day following cessation of teriflunomide treatment have shown that these regimens were effective in accelerating teriflunomide elimination, leading to more than 98% decrease in teriflunomide plasma concentrations, with cholestyramine being faster than charcoal. Following discontinuation of teriflunomide and the administration of cholestyramine 8 g three times a day, the plasma concentration of teriflunomide is reduced 52% at the end of day 1, 91% at the end of day 3, 99.2% at the end of day 7, and 99.9% at the completion of day 11. The choice between the 3 elimination procedures should depend on the patient’s tolerability. If cholestyramine 8 g three times a day is not well-tolerated, cholestyramine 4 g three times a day can be used. Alternatively, activated charcoal may also be used (the 11 days do not need to be consecutive unless there is a need to lower teriflunomide plasma concentration rapidly).
Systemic exposure increases in a dose proportional manner after oral administration teriflunomide from 7 to 14 mg.
Several sources of intrinsic variability were identified in healthy subjects and MS patients based on the PopPK analysis: age, body weight, gender, race, and albumin and bilirubin levels. Nevertheless, their impact remains limited (≤31%).
Mild and moderate hepatic impairment had no impact on the pharmacokinetic of teriflunomide. Therefore no dose adjustment is anticipated in mild and moderate hepatic-impaired patients. However, teriflunomide is contraindicated in patients with severe hepatic impairment (see sections 4.2 and 4.3).
Severe renal impairment had no impact on the pharmacokinetic of teriflunomide. Therefore no dose adjustment is anticipated in mild, moderate and severe renal-impaired patients.
In paediatric patients with body weight >40 kg treated with 14 mg once daily, steady state exposures were in the range observed in adult patients treated with the same dosing regimen.
In paediatric patients with body weight ≤40 kg treatment with 7 mg once daily (based on limited clinical data and simulations) led to steady state exposures in the range observed in adult patients treated with 14 mg once daily.
Observed steady state trough concentrations were highly variable between individuals, as observed for adult MS patients.
Repeated oral administration of teriflunomide to mice, rats and dogs for up to 3, 6, and 12 months, respectively, revealed that the major targets of toxicity were the bone marrow, lymphoid organs, oral cavity/gastro intestinal tract, reproductive organs, and pancreas. Evidence of an oxidative effect on red blood cells was also observed. Anaemia, decreased platelet counts and effects on the immune system, including leukopenia, lymphopenia and secondary infections, were related to the effects on the bone marrow and/or lymphoid organs. The majority of effects reflect the basic mode of action of the compound (inhibition of dividing cells). Animals are more sensitive to the pharmacology, and therefore toxicity, of teriflunomide than humans. As a result, toxicity in animals was found at exposures equivalent or below human therapeutic levels.
Teriflunomide was not mutagenic in vitro or clastogenic in vivo. Clastogenicity observed in vitro was considered to be an indirect effect related to nucleotide pool imbalance resulting from the pharmacology of DHO-DH inhibition. The minor metabolite TFMA (4-trifluoromethylaniline) caused mutagenicity and clastogenicity in vitro but not in vivo.
No evidence of carcinogenicity was observed in rats and mice.
Fertility was unaffected in rats despite adverse effects of teriflunomide on male reproductive organs, including reduced sperm count. There were no external malformations in the offspring of male rats administered teriflunomide prior to mating with untreated female rats. Teriflunomide was embryotoxic and teratogenic in rats and rabbits at doses in the human therapeutic range. Adverse effects on the offspring were also seen when teriflunomide was administered to pregnant rats during gestation and lactation. The risk of male-mediated embryo-foetal toxicity through teriflunomide treatment is considered low. The estimated female plasma exposure via the semen of a treated patient is expected to be 100 times lower than the plasma exposure after 14 mg of oral teriflunomide.
Juvenile rats receiving oral teriflunomide for 7 weeks from weaning through sexual maturity revealed no adverse effects on growth, physical or neurological development, learning and memory, locomotor activity, sexual development, or fertility. Adverse effects comprised anaemia, reduction of lymphoid responsiveness, dose-dependently diminished T cell dependent antibody response and greatly decreased IgM and IgG concentrations, which generally coincided with observations in repeat-dose toxicity studies in adult rats. However, the increase in B cells observed in juvenile rats was not observed in adult rats. The significance of this difference is unknown, but complete reversibility was demonstrated as for most of the other findings. Due to the high sensitivity of animals to teriflunomide, juvenile rats were exposed to lower levels than those in children and adolescents at the maximum recommended human dose (MRHD).
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