Teriflunomide: a new choice in the oral MS drug market?

Aubagio (teriflunomide), a once-daily oral treatment, was recommended for treatment of relapsing forms of multiple sclerosis by the European Medicines Agency in March 2013

David de Monteverde-Robb BSc(Hons) DipPharmPract MSc(ClinRes) MRPharmS ADA

Head of Pharmacy Research,

Clinical Pharmacy Lead for Immunotherapies, Neurosciences and Perioperative Medicine, Addenbrookes Hospital, Cambridge, UK

Email: [email protected]

On 21 March 2013, the European Medicines Agency (EMA) recommended granting marketing authorisation for teriflunomide (L04AA31) for relapsing-remitting multiple sclerosis (MS).(1) However, teriflunomide is not quite as new as first thought. The EMA does not consider that this is a new active substance. Leflunomide, licensed since 1998 for rheumatoid and psoriatic arthritis, is rapidly converted to the primary active metabolite teriflunomide, and several minor inactive metabolites (Figure 1).

As such, much is known about the clinical monitoring of the therapy and the expected side effects, including the effects of long-term administration. There is experience of leflunomide in mild renal insufficiency and in the older population, and it is known that therapy must be avoided in pregnancy. Leflunomide, and therefore teriflunomide, are teratogens; similarly the drug must not be given to breastfeeding women.

Most patients diagnosed with MS will be in a relapsing-remitting phase at the point of diagnosis,(2) so the majority of patients diagnosed with MS would be eligible for treatment within the licensed indication, pending any national restrictions that might apply.

Mode of action

Teriflunomide is an immunosuppressant known to reduce the proliferation of lymphocytes by blocking the mitochondrial enzyme dihydroorotate dehydrogenase (DHO-DH), which is involved in de novo synthesis of the pyrimidines cytosine, thymine and uracil.

This is thought to interfere with the cell cycle progression and proliferation of activated B-cell and T-cell lymphocytes by halting the process in G1. Non-lymphoid cells appear able to utilise an alternative salvage metabolic pathway for the synthesis of ribonucleotides, limiting the risk of a significant cytopenia. The full mechanism of teriflunomide’s effect in MS is not fully understood. The effect of lymphocyte proliferation of the global effect of teriflunomide in MS is thought to be limited as lymphopenia of <2 G/l is rare. Additional theories include inhibition of protein tyrosine kinase and other mechanisms to interfere with lymphocyte migration or cytokine production.(2) Supplementation or dietary intake of thiamine, which is part aminopyrimidine, should have no effect on the actions of teriflunomide. For MS patients, thiamine diphosphate intake is important because it is known to be physiologically relevant in the synthesis of myelin.

Does it work?

The seminal Phase III trial, TEMSO, recruited 1088 patients with clinically definite MS and at least two relapsed in the previous two years or one in the preceding year.(3) The three study arms were: placebo; 7mg daily; 14mg daily (of teriflunomide) for 108 weeks. The results were reported in 2011 and were promising. Relapse rates were significantly reduced versus placebo, as were disability progression and evidence of disease (from magnetic resonance imaging (MRI)). The relative risk reduction of experiencing a relapse versus placebo was 31.2% (7mg daily) or 31.5% (14mg daily). Looking specifically at the number of relapses the patients experienced during the trial, the effect of therapy appeared to be greatest in patients who would have otherwise experienced three or more relapses in the two-year study period.

The stage of MS targeted in the trial is relapsing-remitting so, by definition, a number of patients would not have experienced a relapse regardless of treatment given during the trial, although more patients maintained remission in the treatment groups than placebo (57.8% for 7mg daily and 60.6% for 14mg daily, versus 49.3% for placebo).

The total lesion volumes on T1 weighted MRI with gadolinium (Gd) contrast showed a relative reduction of 39.4% (7mg) and 67.4% (14mg) versus placebo. The significance of these results was particularly good for 14mg daily at p<0.001 although, at p=0.03 for 7mg daily, the evidence for an optimum dose may be emerging. Similarly, the rates of sustained disability progression were only significantly lower in the 14mg daily study arm. The tolerability appears to be acceptable. Although the discontinuation rate in the study was high (26%), the rate was higher in the placebo arm (35%) than in either of the treatment arms.

Results of a small Phase II trial looking at teriflunomide combined with interferon beta in relapsing-remitting MS has been published.(4) Three study arms of placebo, 7mg daily and 14mg daily (of teriflunomide) were used. Recruitment to each arm was 41: 37: 38 respectively with 86 patients in total completing the first 24-week phase of the trial. MRI disease activity (T1-Gd lesion burden) appears reduced in combination therapy compared with interferon-beta alone and therapy appears to be well tolerated. Although the results are promising, the results of ongoing larger trials are awaited to confirm the significance of the results seen.

Adverse effects

Before starting therapy, baseline investigations are required: a pregnancy test for women, a liver function test, complete blood count, a tuberculosis cutaneous test and blood pressure monitoring. The most common side effects are upper respiratory tract infections, urinary tract infections, diarrhoea, nausea, paraesthesia (pins and needles), alopecia (loss of hair) and increase in the liver enzyme alanine aminotransferase. Serious side effects include toxic epidermal necrolysis or cutaneous necrotising vasculitis, hypertension, jaundice or hepatitis, activation of latent infection such as tuberculosis, leukopenia (although this may be desirable), interstitial lung disease and renal failure among others.(5)

There have, to the knowledge of this author, been four documented cases of progressive multifocal leukoencephalopathy secondary to treatment with teriflunomide but none within the published clinical trials. Close ongoing assessment of adverse events will be essential.

Where side effects result in a patient withdrawing from therapy, an elimination protocol is employed (over about 11 days) with cholestyramine ± activated charcoal. This protocol may also be employed to clear the drug from the body in people who elect to stop treatment for the purpose of starting a family.

Pharmacokinetics

Bioavailability is almost 100% with peak concentrations in 1–2 hours of consumption, and delayed by food. Distribution is limited and there is only limited penetration of the blood–brain barrier. Plasma protein binding is almost 99% of the total free and bound concentrations. Teriflunomide is a weak inhibitor of CYP2C9 and it is expected that substrates (for example, phenytoin, warfarin) may have prolonged half-lives, although one study appears to show a 25% decrease in peak international normalised ratio for warfarin-treated patients.(2) The complex interplay between plasma protein binding and CYP450 metabolism, induction and inhibition for teriflunomide, and these narrow therapeutic range drugs requires further investigation.

Owing to the very long plasma T½ for teriflunomide of approximately two weeks (quoted as 15–18 days or approximately equal to the T½ of albumin to which it is 99% bound), it is estimated that steady state plasma concentrations are reached after approximately two months. The elimination T½ is 10–12 days, with approximately 37.5% reported excreted in the faeces, and 22.6% in the urine. The pharmacokinetic profile explains why dose adjustments in the elderly or hepatically impaired are thought to be unnecessary.

The usual dose is 7mg or 14mg orally per day for all patients, and no titration schedules are recommended. The drug is still detectable for up to two years from the cessation of therapy, so long-term contraception will be required for women, unless a detoxification programme with cholestyramine or activated charcoal is employed to maximise the amount of drug lost in the faeces. Physicians and patients will need to consider carefully if this is a therapy that is appropriate for women of childbearing age who might, in the future, wish to bear a child. Men must also wait at least 64 days after stopping therapy before trying to conceive.

Ongoing trials

Several teriflunomide MS trials at the time of writing are either ongoing or as yet unpublished. The TOWER trial is similar in design to TEMSO and evaluates teriflunomide (14mg and 7mg) versus placebo in relapsing remitting MS, but has a prolonged extension phase to evaluate the long-term safety and efficacy of therapy.6 In the second phase of the trial, all patients are offered the chance to continue or switch to teriflunomide. As yet-unpublished results show no difference between 7mg daily and placebo for disease progression. A significant reduction in annualised relapse rate is expected, and a death was recorded from sepsis in one of the teriflunomide arms, which will focus the importance of ongoing clinical monitoring on complete blood counts. The TENERE trial evaluates teriflunomide (14mg or 7mg) against interferon beta-1a in relapsing-remitting disease.(7)

Released, but as yet unpublished, data show no superiority in time to relapse for any arm, although this is influenced by a lower discontinuation rate in the teriflunomide groups than interferon beta, but a higher relapse rate in the teriflunomide arms (42.4% for 14mg; 23.4% for 7mg: 15.4% interferon beta).(8) More details are awaited but results indicate that the 7mg dose is again inferior to 14mg daily and teriflunomide 14mg daily is similar in efficacy to interferon beta-1a as although relapse rates are higher, more patients will continue with therapy. The TERACLES trial was very similar in design to the TENERE trial and has been terminated prior to completion. Presumably this is a commercial decision because there were no identified safety concerns. The TOPIC trial will compare teriflunomide versus placebo in the first clinical episode clinically suggestive of MS.(9)

This outcome of this trial may be a treatment option for patients who would otherwise be untreated until clinically definite MS is established. The clinical data are not yet known but, as this trial focuses on the first clinical episode, even in the light of good efficacy, the financial case for early intervention with this therapy will have to be robust, particularly in nationally funded healthcare systems such as the National Health Service.

Conclusions

Owing to promising published data for relapsing-remitting disease proving efficacy over placebo and the focus of ongoing trials towards early intervention prior to clinically definite disease or combining teriflunomide with interferon beta, there may well be a place for teriflunomide in the growing MS therapies market. The UK National Institute for Health and Care Excellence has restricted fingolimod treatment to people with MS who have failed to sufficiently respond to interferon beta.(10) Teriflunomide may initially be seen as a second therapy option for MS patients initially treated with glatiramer acetate rather than interferon beta, or as an alternative to those who cannot take fingolimod. If economically convincing, perhaps it could be employed as an early intervention in clinical presentations suspicious of MS or with more clinical experience and data perhaps eventually as an alternative to injectable interferon beta. The obvious ease of administration of an oral therapy will appeal to the trypanophobics.

Key points

Although teriflunomide is a new therapy, its potential toxicities and monitoring parameters are well understood due to the historical experience with leflunomide (pro-drug for teriflunomide).
Therapy significantly reduces rates of relapse and MRI evidence of MS lesions in relapsing-remitting MS versus placebo.
7mg dosing is consistently inferior in trials to 14mg daily.
A detoxification program is required prior to conception for both males and females.
Exact place in therapy relative to other available therapies remains to be decided.

References

European Medicines Agency. Summary of opinion: Aubagio (teriflunomide). EMA/167896/2013. www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/002514/WC500144913.pdf (accessed 12 August 2013).
Tanasescu R, Evangelou N, Constantinescu C. Role of oral teriflunomide in the management of multiple sclerosis. J Neuropsychiatric Dis Treatment 2013;9:539–53.
O’Connor P et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis (TEMSO). N Engl J Med 2011;365:1293–303.
Freedman MS et al. Teriflunomide added to interferon-β in relapsing multiple sclerosis: a randomised phase II trial. Neurology 2012;78(23):1877–85.
Genzyme Corporation. Highlights of prescribing information for Aubagio. September 2012. http://products.sanofi.us/aubagio/aubagio.pdf (accessed 12 August 2013).
EU Clinical Trials Register. An efficacy study of teriflunomide in patients with relapsing multiple sclerosis (TOWER). EUDRACT number 2007-004452-36 (NCT00751881). www.clinicaltrialsregister.eu/ctr-search/trial/2007-004452-36/BE (accessed 12 August 2013).
EU Clinical Trials Register. A study comparing the effectiveness and safety of teriflunomide and interferon beta-1a inpatients with relapsing multiple sclerosis (TENERE). EUDRACT number 2008-006226-34 (NCT00883337). www.clinicaltrialsregister.eu/ctr-search/trial/2008-006226-34/HU (accessed 12 August 2013).
Vermersch P. A multicenter, randomized, parallel-group, rater-blinded study comparing the effectiveness and safety of teriflunomide and subcutaneous interferon beta-1a in patients with relapsing MS. Presentation at the 4th co-operative meeting of the Consortium of Multiple Sclerosis Centres (CMSC) and Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) 2012. http://annualmeeting.mscare.org/.
EU Clinical Trials Register. Phase III study with teriflunomide versus placebo in patients with first clinical symptom of multiple sclerosis (TOPIC). EUDRACT number 2006-001152-12 (NCT00622700). www.clinicaltrialsregister.eu/ (accessed 12 August 2013).
National Institute for Health and Care Excellence. Fingolimod for the treatment of highly active relapsing-remitting multiple sclerosis. NICE technology appraisal guidance 254 (April 2012). http://guidance.nice.org/ta254 (accessed 12 August 2013).

Teriflunomide: a new choice in the oral MS drug market?

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