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Abstract
▼Teriflunomide (Aubagio—Genzyme Therapeutics), the main metabolite of the disease-modifying anti-rheumatic drug leflunomide,1 is an immunomodulatory agent with anti-inflammatory properties.2 It is a new oral treatment licensed for adults with relapsing-remitting multiple sclerosis. Here we discuss the evidence for its effectiveness and safety, and consider its place in therapy.
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Background
Multiple sclerosis (MS) is a chronic, progressive neurodegenerative disorder with multifocal demyelination affecting the brain and spinal cord. The relapsing-remitting form of the disease is the most common presentation, affecting around 80% of patients at onset.3 Approximately 60–70% of those with relapsing-remitting MS will have conversion to secondary progressive MS, usually 1–3 decades after disease onset.4
Drug treatment for MS
In 2002, the National Institute for Health and Care Excellence (NICE) reviewed the clinical and cost-effectiveness of interferon beta and glatiramer, and concluded that neither drug could be recommended for the treatment of MS in the NHS in England and Wales.5 Subsequently, these medicines were made available across the UK through a risk-sharing scheme for patients meeting criteria agreed by the Association of British Neurologists (see Box),6,7 and their use has become established practice in the NHS.8 Clinical trials have shown that interferon beta and glatiramer reduce relapse frequency in patients with relapsing-remitting MS by about 30% (equivalent to approximately one relapse avoided every 2.5 years).5 More recently, ▼natalizumab (2006), ▼alemtuzumab (2013), ▼fingolimod (2011) and ▼dimethyl fumarate (2014) have been licensed for treatment of relapsing-remitting MS.9–12 Their use in the NHS is subject to approval by the separate devolved UK health services.
Box: Summary of eligibility criteria for treatment with interferon beta or glatiramer3
People with relapsing-remitting multiple sclerosis should be offered interferon beta (any type) or glatiramer provided that the following four conditions are met:
ability to walk 100m or more without assistance
at least two clinically significant relapses in the past 2 years
aged 18 years or older
no contraindication to treatment
What is teriflunomide?
Teriflunomide acts as a selective, reversible inhibitor of dihydroorotate dehydrogenase (a key enzyme involved in de novo pyrimidine synthesis),2 and may also have additional effects which account, at least in part, for its observed immunomodulatory activity.13 Although the exact mechanism of action for the therapeutic effect in MS is unknown, it is thought to involve a reduction in the number of activated lymphocytes in the CNS.1
Teriflunomide was launched in the UK in January 2014 for the treatment of adults with relapsing-remitting MS.2,14 The licensed dose is one 14mg tablet taken orally once daily; treatment should be initiated and supervised by a physician experienced in the management of MS.2
Evaluating treatments for MS in clinical trials
The European Medicines Agency's (EMA's) guidance on the development of drugs for MS identifies the following as meaningful treatment goals for patients with relapsing-remitting disease:15
prevention and/or modification of relapse features;
prevention or delay of the accumulation of disability.
The EMA advises that the most relevant parameter is the accumulation of disability, which usually takes place over many years.15 The Kurtzke Expanded Disability Status Scale (EDSS; range: 0 [best] to 10 [worst]), is the most widely used scale to assess changes in disability in MS. It does however have some disadvantages, including limited inter- and intra-observer reliability,15 and insensitivity to important clinical and diagnostic changes (i.e. arm function, cognition and changes revealed by magnetic resonance imaging [MRI]).16
In patients with relapsing MS, the primary endpoint of clinical trials may also be the annualised relapse rate, although the number, duration or severity of relapses cannot be taken as a surrogate for disease progression. The EMA recommends that a maintained effect on relapses should be demonstrated, at least during 2 years.15
Although MRI is a useful tool for monitoring CNS lesions in MS and different parameters have been related to clinical activity, MRI measurements have not been proven to be a reasonably validated surrogate endpoint of clinical outcomes.15
Clinical efficacy
The licensing submission included two phase III studies (TEMSO and TOWER) that compared teriflunomide with placebo and one phase III study that compared teriflunomide with interferon beta-1a (TENERE).17 All three studies18–20 included adults (aged 18–55 years [TEMSO and TOWER], ≥18 years [TENERE]) with relapsing MS (mainly relapsing-remitting), with or without progression, who had experienced at least one relapse in the previous 12 months or two or more in the previous 24 months (TEMSO and TOWER), and who had an EDSS score of ≤5.5 points.i Those who had a relapse within 30 days (TOWER and TENERE) or 60 days (TEMSO) before randomisation were excluded, as were those who had ever received natalizumab or other immunosuppressants. Previous use of cytokine therapy, interferon beta or glatiramer acetate was permitted, as long as it was stopped at least 3 months (TOWER and TENERE) or 4 months (TEMSO) prior to study entry.
The studies evaluated two doses of teriflunomide (7mg and 14mg once daily) but in this article only the results for the licensed dose (14mg) are presented.
Compared with placebo
A randomised double-blind trial (TEMSO; n=1,088) compared teriflunomide with placebo over 108 weeks.18 The primary efficacy endpoint was the number of confirmed relapses per patient-year (annualised relapse rate), with a relapse defined as new or worsening clinical signs or symptoms lasting at least 24 hours without fever. Confirmed relapses required an increase of 1 point in each of two EDSS functional-system scores or of 2 points in one score (excluding bowel and bladder function and cerebral function), or an increase of 0.5 points in the EDSS score from the previous clinically stable assessment. The main secondary endpoint was 3-month sustained progression of disability, defined as a 1-point increase in EDSS score from baseline that persisted for at least 12 weeks.
In the modified intention-to-treat (mITT) population of patients who underwent randomisation and received study medication for at least 1 day (n=1,086), teriflunomide reduced the annualised relapse rate by 0.17 relapses per patient-year compared with placebo (0.37 vs. 0.54, p<0.001). The proportion of patients with sustained disability progression was also lower for teriflunomide (20.2% vs. 27.3% with placebo; hazard ratio [HR] 0.70; 95% CI 0.51 to 0.97, p=0.03).18
The TEMSO extension study included 742 patients who completed the initial phase. An interim analysis performed 5 years after initial randomisation indicated that the treatment effect of teriflunomide was maintained over this period.21 However, the interim results of the extension study have only been published as a poster presentation.
A second randomised placebo-controlled double-blind study (TOWER; n=1,169) involved a variable follow-up period (minimum of 48 weeks).19 In the mITT population (n=1,165) teriflunomide reduced the adjusted annualised relapse rate by 0.18 relapses per patient-year compared with placebo (0.32 vs. 0.50, p=0.0001). The risk of 3-month sustained accumulation of disability was also lower with teriflunomide (HR 0.68, 95% CI 0.47 to 1.00, p=0.0442).
Compared with interferon beta-1a
A randomised, rater-blinded study (TENERE; n=324) compared oral teriflunomide (double-blind with respect to the two dose groups) with open-label subcutaneous interferon beta-1a (Rebif; three times per week with the dose titrated up to 44mcg if tolerated).20 Treatment was for a minimum of 48 weeks. The primary efficacy endpoint was time to treatment failure, defined as the first occurrence of confirmed relapse or permanent treatment discontinuation for any reason.
In the ITT population, the difference in the probability of treatment failure at week 48 was not statistically significant between those taking teriflunomide 14mg and the interferon beta-1a group (33% vs. 37%, p=0.6). Although the study was not powered to detect differences in the individual components of the primary endpoint, treatment failure was mostly due to permanent treatment discontinuation in the interferon beta-1a group and lack of efficacy in the teriflunomide group.20
There are no fully published studies comparing teriflunomide with glatiramer acetate, nor with any other disease-modifying therapy.
Limitations of the data
Although both placebo-controlled studies showed a relative risk reduction for the primary outcome (annualised relapse rate) of >30%, the adjusted annualised relapse rate in the placebo and active treatment groups was low and therefore the absolute reduction in relapse rate was small (<0.2 relapses per year).22
As recovery from relapse may continue for up to 12 months (within 3–4 months on average), assessment of 6-month sustained accumulation of disability is considered to be a more robust outcome measure than the 3-month assessment.8,15 The 6-month assessment in both TEMSO and TOWER was not statistically significantly different when compared with placebo.8
There was no significant difference in measures of fatigue or quality of life with teriflunomide compared with placebo; such outcomes may be of greater importance than relapse rate to individuals living with MS.22
TEMSO and TOWER were relatively short studies, considering the long duration of the disease and infrequency of relapses; they may therefore not adequately capture differences in relapse rates. In addition, this limits the assessment of any differences in mortality and in less frequently reported adverse events. The studies only included patients aged up to 55 years, and it is not known if the results are generalisable to an older population.22
As the TENERE study was not designed to compare the effectiveness of teriflunomide with interferon beta-1a,8 the comparative effectiveness of these two agents remains unknown.
Unwanted effects
In the pooled safety population from placebo-controlled studies (including 415 patients who took teriflunomide 14mg; treated for up to 2 years), the most commonly reported adverse events (versus placebo) included diarrhoea (17.3% vs. 8.3%); alopecia (14.7% vs. 4.3%); nausea (14.2% vs. 6.9%); increased alanine aminotransferase (ALT) (14.0% vs. 7.1%); influenza (11.8% vs. 9.3%), upper respiratory tract infection (10.8% vs. 9.0%); paraesthesia (10.6% vs. 7.8%) and urinary tract infection (10.6% vs. 9.5%).2,17
Although increases in ALT >3 times the upper limit of normal (ULN) were seen in a similar proportion of patients treated with teriflunomide and placebo, mild increases (>1 to ≤3 times ULN) were more frequent (49.6% vs. 29.5%, respectively), and were seen most commonly within the first 6 months.2 Data indicated that this could be reversible but required a rather long recovery time (up to 2 years).17 The summary of product characteristics (SPC) recommends that liver enzymes be checked before initiation, every 2 weeks during the initial 6 months of treatment, and then every 8 weeks thereafter or as indicated by clinical signs and symptoms.2 This is a potential disadvantage for the patient in terms of increased clinic visits and for the service in terms of resources required for increased monitoring.22
Teriflunomide results in a dose-dependent decrease in white blood cell count (<15% from baseline levels, mainly neutrophil and lymphocyte count decrease).17 In clinical trials this occurred during the first 6 weeks then stabilised over time while on treatment but at decreased levels.2 As a drug with immunosuppressant potential, it may increase the risk of infection;1 however, it was not associated with any increase in serious infections in the placebo-controlled studies.2 It should be noted that ‘sporadic cases’ of tuberculosis and cytomegalovirus (CMV) hepatitis infection were reported.17
As teriflunomide is a metabolite of leflunomide, the safety profile of leflunomide may be pertinent when prescribing teriflunomide for patients with MS.2
Cautions and contraindications
Teriflunomide is contraindicated in patients with severe immunodeficiency or significantly impaired bone marrow function; severe hepatic impairment; severe active infection; severe renal impairment undergoing dialysis; and in severe hypoproteinaemia (as it is highly protein bound17).2 It should also not be used during pregnancy or breastfeeding, and women of child-bearing potential are required to use reliable contraception during treatment and thereafter, as long as plasma concentration of teriflunomide is above 0.02mg/L.2
Under the terms of the marketing authorisation for teriflunomide, the company is required to provide all healthcare professionals who intend to prescribe the drug with the SPC, educational materials and an educational card for patients.17 The educational material highlights the need to assess liver function, blood pressure and haematological parameters, as well as monitoring for infections. As there is a potential risk of teratogenicity, pregnancy status should be checked before starting treatment and patients provided with education on effective contraception.
National guidance
NICE has approved teriflunomide for the treatment of adults with active relapsing-remitting MS ("normally defined as two clinically significant relapses in the previous 2 years") for whom interferon beta and glatiramer acetate would otherwise be considered as treatment options; that is those with active disease, who do not have highly active or rapidly evolving severe relapsing-remitting MS. There was inadequate evidence to allow determination of the effectiveness of teriflunomide compared with fingolimod for highly active disease or natalizumab for rapidly evolving disease, and NICE therefore does not recommend its use in these forms of relapsing-remitting MS.8
The Scottish Medicines Consortium has also recommended teriflunomide for the treatment of adults with relapsing-remitting MS, as an alternative to treatment with interferon beta or glatiramer acetate. The drug advice notes that it is not expected to be used for the treatment of patients with highly active disease.22
Teriflunomide is also approved for use in Northern Ireland in line with the NICE appraisal.23
Cost
The list price for teriflunomide is £13,529 per patient/year compared with £6,701 per patient/year for glatiramer and £7,259–£10,572 per patient/year for interferon beta.24,25 In England, Wales and Scotland teriflunomide will be available to the NHS at a discounted price through an agreed patient access scheme. The size of the discount is in confidence and no details have been made public.8,22
Conclusion
▼Teriflunomide is a new oral immunomodulatory agent licensed for the treatment of relapsing-remitting multiple sclerosis. In studies lasting around 2 years it has been shown to result in an absolute reduction of about 0.2 relapses per patient-year compared with placebo. The relative reduction in relapse rate of 30% is similar to the effect seen in studies of glatiramer acetate or interferon beta. Despite benefits in terms of relapses, it is not yet known if this will translate into a long-term reduction in disability. One study failed to show a statistically significant difference between teriflunomide and interferon beta-1a in terms of treatment failure based on a combined endpoint of relapse or permanent treatment discontinuation. However, this study was not designed to compare the effectiveness of the two treatments. There are no published head-to-head studies with other agents, and it is therefore difficult to determine its exact place in therapy at this stage.
A range of adverse effects have been reported and prescribers are required to regularly monitor liver function, blood pressure, blood count as well as monitoring patients for infections. In addition, teriflunomide is contraindicated in patients with severe immunodeficiency, severe hepatic impairment, severe active infection, severe renal impairment undergoing dialysis, severe hypoproteinaemia and in women who are pregnant, those of child-bearing potential who are not using effective contraception, and in women who are breastfeeding.
Teriflunomide costs £13,531 per patient/year. In England, Scotland and Wales it has been approved for use in the NHS provided that the company makes it available at a discounted price. However, the details of the level of discount are not in the public domain.
The long-term benefits and safety profile of teriflunomide need further assessment. Disability resulting from multiple sclerosis usually accumulates over many years and the safety of a disease-modifying therapy requires long-term monitoring. Teriflunomide should only be prescribed by specialists in the management of multiple sclerosis, and in our opinion should be reserved for patients not able to tolerate first-line treatment with interferon beta or glatiramer.