Steve Chaplin

The Association of British Neurologists’(ABN) management guideline recom-

mends beta interferon or glatirameracetate (GLAT) as first-line therapy foradults with active relapsing-remitting multiple sclerosis (RRMS) that is not rap-idly evolving.1 Both treatments are admin-istered by injection, which is a barrier toadherence for some patients.2–4 NICE hasnow recommended oral teriflunomide asan option for first-line therapy.2

The ABN guideline will soon be out ofdate, and current practice is for cliniciansand patients to choose a drug, taking intoaccount the course and severity of thepatients’ MS, lifestyle issues, route andschedule of administration, the side-effectprofile and storage requirements.5 Dimethylfumarate (DMF; Tecfidera), another oraldrug for patients with RRMS, is likely to beNICE approved soon, and will be an alter-native first-line therapy for people withRRMS who do not qualify for treatment withnatalizumab. DMF could also have a roleafter failure of an interferon or GLAT.5

Dimethyl fumarateDMF has been licensed by the EMA andFDA for treatment of adults with RRMS.Its mechanism of action is uncertain butappears to be mediated through activa-tion of the nuclear factor (erythroid-

derived 2)-like 2 (Nrf2) transcriptionalpathway, promoting anti-inflammatoryactivity and inhibiting pro-inflammatorycytokines and adhesion molecules.

Treatment is initiated at a dosage of120mg twice daily with food, increasedto 240mg twice daily after one week.Renal and hepatic function should beassessed before treatment, after threeand six months, and then every six to 12months. DMF may decrease the lympho-cyte count; a full blood count is recom-mended before treatment, after sixmonths, and then every six to 12 months.

No dose adjustment is recommendedfor the elderly, nor in patients withimpaired renal or hepatic function, how-ever DMF should be prescribed with cau-tion in older people. It is contraindicatedin patients with severe renal or hepaticimpairment or severe active gastrointesti-nal disease, and during pregnancy.

Clinical trialsTwo phase 3 trials have compared DMF240mg twice daily with placebo: DEFINE(n=1234)6 and CONFIRM (n=1417).7 Bothtrials included a three times daily treat-ment arm, but only data for the twice daily

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Dimethyl fumarate for relapsing-remitting multiple sclerosisSteve Chaplin BPharm, MSc, Klaus Schmierer PhD, FRCP

Dimethyl fumarate is thethird oral disease-modifyingtreatment for people withRRMS. Steve Chaplinpresents the data relating to its efficacy and adverseevents and Klaus Schmiereroutlines its place in therapy.

KEY POINTS

n dimethyl fumarate (Tecfidera) is licensed for the treatment of adults with relapsing-remitting multiple sclerosis

n it has anti-inflammatory properties but its mechanism of action is uncertain

n the recommended dosage is initially 120mg then 240mg twice daily orally with food

n a month’s treatment on the maintenance dose costs £1373

n compared with placebo, it significantly reduced relapse rates and new brainlesions after two years’ treatment

n a reduction in disability progression has not consistently been shown in the twopivotal phase 3 trials, although post hoc analyses suggest such an effect

n common adverse effects include flushing and gastrointestinal events, low whitecell count, pruritus, rash and proteinuria

dose are discussed here. CONFIRMincluded GLAT 20mg per day as a ‘refer-ence’ but was not designed to assesswhether DMF was superior or non-inferior.

Both trials included patients aged 18–55 with RRMS, and a score of ≤5 onthe Expanded Disability Status Scale(EDSS), plus at least one clinically docu-mented relapse in the previous 12 monthsor at least one gadolinium-enhancinglesion up to six weeks before randomisa-tion. The primary endpoint of DEFINE wasthe proportion of patients who had arelapse by two years; for CONFIRM, it wasthe annualised relapse rate (ARR) at twoyears. About 20 per cent of patients ineach study discontinued treatment.

In DEFINE, relapses occurred in sig-nificantly fewer patients treated with DMF(27 vs 46 per cent with placebo,p<0.001); the ARR after two years was0.17 compared to 0.36 with placebo(p<0.001). DMF prolonged the time tofirst relapse (87 vs 38 weeks withplacebo in the 25th percentile ofpatients) and reduced the risk of con-firmed disability progression over twoyears (hazard ratio 0.62, 95 per cent CI,0.44–0.87; p=0.005). On MRI, DMFreduced the mean numbers of new orenlarging T2-weighted lesions at twoyears (2.6 vs 17.0 with placebo) and

gadolinium-enhancing T1-weightedlesions (0.1 vs 1.8).

In CONFIRM, the ARR was 0.22 withDMF and 0.40 with placebo (p<0.001);the ARR for GLAT was 0.29. The propor-tions of patients with relapse after twoyears were 29, 41 and 32 per cent,respectively. Neither DMF nor GLAT sig-nificantly reduced disability progressionat six months. The mean number of new

or enlarging T2-weighted lesions on MRIat two years was reduced by DMF (3.0 vs7.0 with placebo; 4.1 with GLAT); it alsoreduced the number of gadolinium-enhancing lesions on T1-weighted MRI(0.5 vs 2.0; 0.7 with GLAT).

Adverse eventsThe most frequently reported adverseevents are flushing (affecting one third of

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38 z Prescriber December 2014 prescriber.co.uk

Patie

nts

with

rela

pse

(%)

100

90

80

70

60

50

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0 12 24 36 48 60 72 84 96Weeks on study

Twice daily DMF

Placebo

Figure 1. Time to confirmed first relapse and proportion of patients with confirmed relapseamong the DMF twice daily and placebo groups in the DEFINE trial.6

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Place in therapyKlaus Schmierer

DMF is a welcome addition to the newbatch of disease-modifying treatments(DMTs) for people with RRMS. It is the third oral DMT available to patientson the NHS, and the second first-line DMTfollowing the recent release of terifluno-mide (fingolimod is licensed only forRRMS failing treatment with first-lineinjectable DMT).

DMF reduces the relapse rate acrossa broad spectrum of people with RRMS,1

however its potential is probably greatestin recently diagnosed patients,2 ie not inpeople with rapidly evolving or highlyactive RRMS, for whom other treatments(natalizumab, alemtuzumab) will be moreappropriate.

While there is unequivocal evidencefor a significant effect on relapses (about50 per cent reduction relative to placebo),efficacy on disability endpoints has so farbeen less convincing and awaits confir-mation following longer term observation.However, taking into account the signifi-cant effect of DMF on relapses and MRIpredictors of disability, such as the num-ber of T1 hypo-intense lesions (‘blackholes’), and brain atrophy (30 per cent rel-ative reduction compared to placebobetween months 6 and 24), it is likely thatDMF will also be effective in limiting

disability progression. 3 The data collectedso far suggest that DMF is more effectivethan GLAT and – albeit not compareddirectly – beta-interferons. It is thereforelikely that the use of first injectable DMT (GLAT and beta-interferons) willdiminish substantially.

Key adverse effects of DMF are flush-ing, abdominal pain, diarrhoea, nausea,pruritus, proteinuria and lymphopenia.Although these appear manageable in most cases, and gastrointestinal side-effects diminish over about onemonth, one should expect that about 20per cent of patients will not tolerate DMFlong term.

The twice-daily dosing frequency is aslight disadvantage compared to drugsthat need to be taken only once daily.However, neither this minor inconven-ience, nor the overall modest side-effectprofile are likely to impact on the uptakeby UK neurologists eager to prescribeDMF to their patients with RRMS.

As this article goes into press a caseof progressive multifocal leuken-cephalopathy (PML) has been reported ina patient with MS who eventually died ofpneumonia. Apparently, the patient hadbeen taking DMF for more than five yearsand developed significant long term lym-phopenia. Lymphopenia is a known riskfactor for PML, and our empiric advice atthis stage would be to prevent the lympho-cyte count in patients treated with DMF

from dropping lower than 0.8x109 per litre(WHO grade 1–2 toxicity).4

References1. Hutchinson M, et al. Clinical efficacy of BG-12 (dimethyl fumarate) in patients withrelapsing–remitting multiple sclerosis: sub-group analyses of the CONFIRM study. J Neurol2013;260:2286–96.2. Gold R, et al. Efficacy and safety of delayed-release dimethyl fumarate in patients newly diag-nosed with relapsing-remitting multiple sclerosis(RRMS). Mult Scler J 2014 Jul 2 (Epub ahead ofprint; 10.1177/ 1352458514537013).3. Arnold DL, et al. Effects of delayed-releasedimethyl fumarate on MRI measures in thePhase 3 DEFINE study. J Neurol 2014 Sep;261:1794–802.4. http://multiple-sclerosis-research.blogspot.com/2014/10/clinicspeak-pml-and-dimethyl-fumarate_24.html

Declaration of interestsDr Schmierer has received speaker feesand honoraria from, and/or served onadvisory boards for Novartis, Biogen,Teva, Merck-Serono and Merck Inc, andhas received travel support fromGenzyme.

Reader in Clinical Neurology andConsultant Neurologist (Hon) at theBlizard Institute (Neuroscience), QueenMary, University of London and TheRoyal London Hospital, Barts HealthNHS Trust

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patients vs 4 per cent with placebo), diar-rhoea, abdominal pain and nausea (10–14 per cent vs 6–10 per cent withplacebo). These usually begin in the firstmonth of treatment and intermittentlythereafter, causing 3–4 per cent ofpatients to stop treatment. Flushing andadverse gastrointestinal effects may bereduced by lowering the dosage to120mg twice daily for up to one month.Other common adverse events includelow white cell count (not associated withan increased risk of infection), pruritus,rash, proteinuria and raised liverenzymes.

References1. Association of British Neurologists.Revised (2009) guidelines for prescribing in

multiple sclerosis. November 2009(www.mstrust. org.uk/competencies/down-loads/abn_ms_guidelines_2009_final.pdf;accessed 11 November 2014).2. NICE. Teriflunomide for treating relapsing-remitting multiple sclerosis. NICE TechnologyAppraisal No. 303. January 2014 (www.nice.org.uk/guidance/ta303/resources/guid-ance-teriflunomide-for-treating-relapsin-gremitting-multiple-sclerosis-pdf; accessed11 November 2014).3. Remington G, Rodriguez Y, Logan D, et al.Facilitating Medication Adherence inPatients with Multiple Sclerosis. Int J MSCare 2013;15:36–45.4. Costello K, Kennedy P, Scanzillo J.Recognizing nonadherence in patients withmultiple sclerosis and maintaining treat-ment adherence in the long term. MedscapeJ Med 2008;10:225.5. NICE. Dimethyl fumarate for treating

relapsing-remitting multiple sclerosis.August 2014 (https://www.nice.org.uk/gui-dance/ta320/resources/guidance-dimethyl-fumarate-for-treating-relapsingremitting-multiple-sclerosis-pdf; accessed 11 November2014).6. Gold R, Kappos L, Arnold DL, et al.Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl JMed 2012;367:1098–107.7. Fox RJ, Miller DH, Phillips JT, et al.Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. NEngl J Med 2012;367:1087–97.

Declaration of interestsSteve Chaplin has none to declare.

Steve Chaplin is a pharmacist who specialises in writing on therapeutics