1Optimizing Early Therapy:Future Options and ConsiderationsGavin GiovannoniBernd Kieseier
Disclosures▪ Professor Giovannoni has provided consultation toBayer-Schering Healthcare, Biogen-Idec, Genzyme,GlaxoSmithKline, Merck-Serono, Novartis, ProteinDiscovery Laboratories, Teva-Aventis, UCB Pharma.Ironwood, Eisai, Vertex, Roche, Synthon, Canbex. Hehas received grant support from Bayer-ScheringHealthcare, Biogen-Idec, Merck-Serono, Merz, Novartis,Teva-Aventis, GW Pharma▪ Professor Kieseier has provided consultation to BayerSchering, Biogen Idec, Medac, Merck Serono, Novartis,Sanofi-Aventis, Talecris, Teva. He has received grantsupport from Bayer Schering, Biogen Idec, Biotest,Merck Serono, Teva2
CHMP Opinion: Dimethyl FumarateCategory OpinionIndication Treatment of adult patients with relapsing remitting multiple sclerosisActivesubstanceDimethyl fumarate, a nervous system drug (N07XX09), that primarilyacts by triggering the activation of the nuclear factor (erythroid-derived2)-like 2 (Nrf2) transcriptional pathway.BenefitsAbility to reduce the number of relapses in patients with relapsing-remitting multiple sclerosisMost commonside effectsFlushing and gastrointestinal events (eg, diarrhea, nausea, andabdominal pain)4Detailed recommendations for the use of this product will be described in the summary of product characteristics (SmPC), which will bepublished in the European public assessment report (EPAR) and made available in all official European Union (EU) languages after themarketing authorization has been granted by the European Commission (EC).CHMP=Committee on Human Medicinal Products.▪ A pharmacovigilance plan will be implemented▪ Treatment should be initiated under the supervision of a physician experienced in thetreatment of the disease
Dimethyl Fumarate: Research into Mechanism ofAction Concurrent with Clinical Development5Inflammation,tissue damageNrf2Cell tissue andcytoprotectionProtectiveresponse againstneurotoxic insultDimethyl FumarateAnti-inflammatoryresponseScannevin RH et al. J Pharmacol Exp Ther. 2012;341:274-284; Kappos L et al. Lancet. 2008;372:1463−1472;Gold R et al. N Engl J Med. 2012;367:1098−1107; Fox RJ et al. N Engl J Med 2012;367:1087−1097.Transcriptional profiling suggestsdimethyl fumarate activates theNrf2 Oxidative Stress ResponsePathwayWT Nrf2 Knockout02004006008007GenesInducedbyDMF4hrTreatment(p<10-5)Confirmation in Nrf2 Knockout Mice
*Any patient with significant protocol-defined disability progression may switch to open-label MS treatment at any time; CONFIRM: any patient with 2INEC-confirmed relapses at any time may switch to open-label MS treatment after 48 weeks on study; †double-blind only for dimethyl fumarate andplacebo; rater-blinded for all arms; INEC fully blinded to all arms.DEFINE=Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS; CONFIRM=Comparator and an Oral Fumarate inRelapsing-Remitting MS; PO=by mouth; TID=3 times daily; BID=twice daily; GA=glatiramer acetate; SC=subcutaneous; INEC=independent neurologyevaluation committee.Gold R et al. N Engl J Med. 2012;367:1098-1107; Fox R et al. N Engl J Med. 2012;367:1087-1197.*Any patient with significant protocol-defined disability progression may switch to open-label MS treatment at any time; DEFINE: any patient with 1 INEC-confirmed relapse on or after week 24 may switch to open-label MS treatment after 48 weeks on study; †double-blind only for dimethyl fumarate andplacebo; rater-blinded for all arms; INEC fully blinded to all arms.Dimethyl Fumarate Phase 3 Study Schematic:DEFINE and CONFIRM7Screening240 mg PO BID (480 mg/day)240 mg PO TID (720 mg/day)Optional open-label MS treatment*PlaceboRandomization1:1:1Year 1 Year 2GA SC (20 mg/day)Multicenter, double-blind, dose-comparison study(N=1237; MRI N=540)Multicenter, double-blind, reference comparator,dose-comparison study (N=1430; MRI N=681)†Randomization1:1:1:1
0.400.220.200.2900.10.20.30.40.50.6Placebo(n=363)240 mg BID(n=359)240 mg TID(n=345)GA(n=350)0.360.17 0.1900.10.20.30.40.50.6Placebo(n=408)240 mg BID(n=410)240 mg TID(n=416)44%reductionvs placeboP<0.00151%reductionvs placeboP<0.001*Annualized relapse rate calculated with negative binomial regression, with prespecified adjustment for baseline EDSS score (≤2.0 vs >2.0),baseline age (<40 vs ≥40 years), region, and number of relapses in the 1 year prior to study entry; data after switch to alternative MS therapywere excluded; Gold R et al. N Engl J Med. 2012;367:1098-1107; Fox R et al. N Engl J Med. 2012;367:1087-1197.29%reductionvs placeboP<0.05Annualized Relapse Rate at 2 Years853%reductionvs placeboP<0.00148%reductionvs placeboP<0.001AnnualizedRelapseRate*(95%CI)AnnualizedRelapseRate*(95%CI)CONFIRMDEFINE
New or Newly EnlargingT2-Hyperintense Lesions at 2 Years*9*Negative binomial regression analysis, adjusted for region and baseline T2 lesion volume.Gold R et al. N Engl J Med. 2012;367:1098-1107; Fox R et al. N Engl J Med. 2012;367:1087-1197.NeworNewlyEnlargingT2Lesions*(mean)17.02.64.40510152025Placebo(n=165)240 mg BID(n=152)240 mg TID(n=152)NeworNewlyEnlargingT2Lesions*(mean)74%reductionvs placeboP<0.00185%reductionvs placeboP<0.00117.45.1 4.78.00510152025Placebo(n=139)240 mg BID(n=140)240 mg TID(n=140)GA(n=153)71%reductionvs placeboP<0.00173%reductionvs placeboP<0.00154%reductionvs placeboP<0.001CONFIRMDEFINE
Gd+ Lesions at 2 Years*10*Ordinal logistic regression analysis, adjusted for region and baseline number of Gd+ lesions.Gd+=gadolinium-enhancing.Gold R et al. N Engl J Med. 2012;367:1098-1107; Fox R et al. N Engl J Med. 2012;367:1087-1197.Gd+Lesions(mean)22.214.171.124.00.51.01.52.02.5Placebo (n=165) 240 mg BID(n=152)240 mg TID(n=152)Gd+Lesions(mean)2.00.50.40.70.00.51.01.52.02.5Placebo(n=144)240 mg BID(n=147)240 mg TID(n=144)GA(n=161)73%reductionvs placeboP=0.00190%reductionvs placeboP<0.00174%reductionvs placeboP<0.00165%reductionvs placeboP=0.00161%reductionvs placeboP=0.001CONFIRMDEFINE
New T1-Hypointense Lesions at 2 Years*11NewT1-HypointenseLesions*(mean)126.96.36.19910Placebo (n=165) 240 mg BID(n=152)240 mg TID(n=152)NewT1-HypointenseLesions*(mean)7.03.02.44.10510Placebo(n=139)240 mg BID(n=140)240 mg TID(n=140)GA(n=154)*Negative binomial regression analysis, adjusted for region and baseline T1 lesion volume.Arnold DL et al. Presented at ECTRIMS, October 19–22, 2011. Amsterdam, The Netherlands. P831; Fox R et al.N Engl J Med. 2012;367:1087-1197.63%reductionvs placeboP<0.00172%reductionvs placeboP<0.00157%reductionvs placeboP<0.00165%reductionvs placeboP<0.00141%reductionvs placeboP<0.001CONFIRMDEFINE
12-Week Confirmed Disability Progression12*Estimated proportion of patients with progression and time to progression up to 96 weeks based on the Kaplan-Meier product limit method;†based on Cox proportion hazards model, adjusted for baseline EDSS score (≤2.0 vs >2.0), region, and baseline age (<40 vs ≥40 years).Gold R et al. N Engl J Med. 2012;367:1098-1107; Fox R et al. N Engl J Med. 2012;367:1087-1197.PatientswithDisabilityProgression*(%)12 24 36 48 60 72 84 96Time on Study (weeks)0102030 240 mg BID=38% risk reduction, P=0.005†240 mg TID=34% risk reduction, P=0.013†181627BLPlacebo240 mg BID240 mg TID12 24 36 48 60 72 84 96Time on Study (weeks)0240 mg BID=21% risk reduction, P=0.25†240 mg TID=24% risk reduction, P=0.20†GA=7% risk reduction, P=0.70†1617BLPlacebo240 mg BID240 mg TID13GA102030PatientswithDisabilityProgression*(%)13CONFIRMDEFINE
Dimethyl Fumarate Activation of the Nrf2Pathway in MS Patients13Changes of Blood NQO1 Over Timein DEFINE Phase 3 Trial0 10 20 30 40 50-5%0%5%10%15%20%25%30%35%PlaceboBIDTIDWeekNormalized%ChangeNQO1*****P<0.05 compared with placebo.NQO1=NADPH (nicotinamide adenine dinucleotide phosphate) quinone oxidoreductase; BID=twice daily; TID=3 times daily.Biogen Idec, data on file.
Integrated Analysis: Overview of Safety*14Event, % PatientsPlacebo(n=836)240 mg BID(n=769)240 mg TID(n=823)Any adverse event 92 95 93Serious adverse event† 21 18 15Discontinuation due to adverse event 11 14 14Study withdrawal due to adverse event 4 8 8Infection 56 60 60Serious infection 1.4 2.2 1.8Malignancy <1 <1 <1Death <1‡ <1§ <1¶*The safety population for the integrated analysis includes patients treated with placebo or dimethyl fumarate 240 mg TID from the phase 2 dose-ranging study, as well as all patients from the phase 3 studies, DEFINE and CONFIRM; †includes MS relapses fitting the classification of a seriousadverse event; ‡due to ischemic stroke after switch to alternative MS medication; §due to road traffic accident/traumatic brain injury after studywithdrawal; ¶due to road traffic accident and MS relapse complicated by intraventricular hemorrhage after last dose (within 30 days of studywithdrawal).Selmaj K et al. Presented at ECTRIMS; October 10–13, 2012; Lyon, France. P484.
Integrated Analysis: Common Adverse Events(≥10% in Any Group)15Event, % PatientsPlacebo(n=836)240 mg BID(n=769)240 mg TID(n=823)Flushing 5 34 29MS relapse 43 29 26Nasopharyngitis 20 22 22Headache 16 17 17Diarrhea 10 14 17Urinary tract infection 11 14 12Upper respiratory tract infection 11 13 12Nausea 9 12 14Fatigue 11 12 13Back pain 11 12 10Abdominal pain upper 6 10 11Proteinuria* 7 9 10The overall incidence of any GI event was 31%, 40%, and 43% in the placebo, 240 mg BID, and 240 mg TID groups, respectively; *no notable differencesin levels of BUN and creatinine, urine β2-microglobulin, and urine microalbumin were observed across treatment groups with monitoring every 4 weeks.GI=gastrointestinal; BUN=blood urea nitrogen.Selmaj K et al. Presented at ECTRIMS; October 10–13, 2012; Lyon, France. P484.Indicates ≥3% higher incidence in either dimethyl fumarate group vs placebo.
Integrated Analysis: Events Leading to StudyDrug Discontinuation (≥1% in Any Group)16Event, % PatientsPlacebo(n=836)BG-12240 mg BID(n=769)BG-12240 mg TID(n=823)Discontinued study drug 11 14 14MS relapse 6 1 2Flushing <1 3 2GI eventDiarrheaNauseaVomitingAbdominal pain, upperAbdominal pain<1<100<104<1<11<1<1622111Selmaj K et al. Presented at ECTRIMS; October 10–13, 2012; Lyon, France. P484.
Integrated Analysis: Incidence of Flushing Events*and Gastrointestinal Events† by Study Month17*Flushing events included the preferred terms “flushing,” “hot flush,” “erythema,” “generalized erythema,” “burning sensation,” “skin burningsensation,” “feeling hot,” and “hyperemia”; †gastrointestinal events included the preferred terms in the level 2 subordinate standardizedMedDRA queries “gastrointestinal nonspecific inflammations” or “gastrointestinal nonspecific symptoms and therapeutic procedures.”Selmaj K et al. Presented at ECTRIMS; October 10–13, 2012; Lyon, France. P484.Placebo (n=408)240 mg BID (n=410)240 mg TID (n=416)105253035201501 2 3 4 5 6 7 8 9 10 11 12 24MonthPatients(%)3025201510501 2 3 4 5 6 7 8 9 10 11 12 24MonthPatients(%)35Flushing EventsGastrointestinal Events
GI Events in First 3 Months of Treatmentfor BID Dose (n=769)Events, n (%)Abdominal PainAdverse EventsNausea/VomitingAdverse EventsDiarrheaAdverse EventsAny type of this event 121a 120a 78aSeverityMildModerateSevere68 (56)42 (35)11 (9)65 (54)49 (41)6 (5)49 (63)26 (33)3 (4)Symptomatic Therapy 46 (38) 39 (33) 20 (26)Resolvedb 113 (93) 114 (95) 75 (96)18aUsed as the denominator for percentages.; patients may have experienced more than one event. bEvents may have resolved at any time during thestudy. GI events=preferred terms in the level 2 subordinate standardized MedDRA queries: “Gastrointestinal nonspecific inflammations” or“gastrointestinal nonspecific symptoms and therapeutic procedures.”Bar-Or A et al. Presented at LACTRIMS. November 28-30, 2012; Rio de Janeiro, Brazil.
Dimethyl Fumarate Efficacy and Safety:Conclusions▪ Compared with placebo, dimethyl fumarate significantly reduced- Annualized relapse rate and MRI activity- 12-week confirmed disability progression (DEFINE only)- No serious safety signals in ~3600 patient-years exposure▪ Most common adverse events were flushing and GI events- Majority were mild to moderate- Few discontinued treatment (3% due to flushing and 4% due toGI intolerability)- Strategies for management are under further investigation (aspirin,administration with food, dose reduction, symptomatic treatment)19
CHMP Opinion: TeriflunomideCategory OpinionIndication Treatment of adult patients with relapsing-remitting multiple sclerosisActivesubstanceTeriflunomide, a selective immunosuppressant (L04AA31) with anti-inflammatory properties. The exact mechanism by which teriflunomideexerts its therapeutic effect in MS is not fully understood, but it isknown to reduce the proliferation of lymphocytes by blocking themitochondrial enzyme dihydroorotate dehydrogenase (DHO-DH).BenefitsAbility to reduce the relapse rate in patients with relapsing-remittingmultiple sclerosisMost commonside effectsUpper respiratory tract infections, urinary tract infections, diarrhea,nausea, paraesthesia (pins and needles), alopecia (loss of hair) andincrease in the liver enzyme alanine aminotransferase20Detailed recommendations for the use of this product will be described in the summary of product characteristics (SmPC),which will be published in the European public assessment report (EPAR) and made available in all official European Union(EU) languages after the marketing authorization has been granted by the European Commission (EC).▪ A pharmacovigilance plan will be implemented▪ Treatment should be initiated under the supervision of a physician experienced in thetreatment of the disease
ExtensionExtensionExtensionExtensionTeriflunomide Clinical Development ProgramMonotherapy21ExtensionTERACLES: Phase3 adjunctive therapyprogramTEMSO RMS/placeboTOWER: RMS/placeboTENERE: RMS/IFNβTOPIC: CIS/placeboPhase 2 IFN*Phase 2 GAExtensionJune 2012TERIKIDS:pediatric study2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015Adjunctive therapy*Phase 2 study with IFN add-on included any currently available IFNs.Accelerated elimination of teriflunomide by cholestyramine was utilized in all studies, as required.RMS=relapsing multiple sclerosis; IFNβ=interferon beta; CIS=clinically isolated syndrome; GA=glatirameracetate. Data available at http://clinicaltrials.gov. Accessed June 15, 2012.Phase 2 RMS/placebo
TEMSO and TOWER Study Design22RandomizationN=1088Reallocation ofplacebo groupO’Connor PW et al. N Engl J Med. 2011;365:1293-1303; O’Connor PW et al. Presented at: ECTRIMS; October 19–22, 2011; Amsterdam, The Netherlands. P924;Kappos L et al. MS Presented at ECTRIMS. October 10-13, 2012; Lyon, France. P153.14 mg/day14 mg/dayPlacebo (n=363)7 mg/dayTeriflunomide 7 mg/day (n=365)Teriflunomide 14 mg/day (n=358)ScreeningWeek –4 0 12 24 36 48 60 72 84 96 1087 mg/dayRMS patientsscreenedN=1388Entry into extension* orpost-study washoutRandomizationN=1169Placebo (n=388)TeriflunomideTeriflunomideScreeningWeek –4 0 12 24 36 48 60 72 84 96 108 120 132 144 15214 mg/day14 mg/dayExtensionStudy ended when last patient randomized completed 48 weeks of treatmentVariable study treatment duration of 48–152 weeksMinimum treatment timeTEMSOTOWER7 mg/day (n=407)14 mg/day (n=370)
0.540.37 0.3700.10.20.30.40.50.6Teriflunomide: Annualized Relapse Rate23Placebo Teriflunomide7 mgTeriflunomide14 mgAdjusted*AnnualizedRelapseRaten=363 n=365 n=35831.2%P<0.00131.5%P<0.0010.500.390.3300.10.20.30.40.50.6Placebo Teriflunomide7 mgTeriflunomide14 mgAdjusted*AnnualizedRelapseRate n=388 n=407 n=37022.3%P<0.0236.3%P<0.001*Adjusted for EDSS score strata at baseline and takes into account duration of treatment.1O’Connor PW et al. N Engl J Med. 2011;365:1293-1303; 2Kappos L et al. Presented at ECTRIMS; October 10–13, 2012; Lyon, France. P153.TOWER2TEMSO1
Teriflunomide: 12-week SustainedDisability Progression24HRR=hazard ratio reduction1O’Connor PW et al. N Engl J Med. 2011;365:1293-1303; 2Kappos L et al. MS Presented at ECTRIMS; October 10–13, 2012; Lyon, France. P153.01020304012-weekSustainedDisabilityProgression(%)0 12 24 36 48 60 72 84 96 108Weeks27.321.720.2PlaceboTeriflunomide 7 mgTeriflunomide 14 mgPlaceboTeri 7 mgTerif14 mg363365358336343329306309302279290285258266262242252251224238234211234227200224217160178175Number of Patients at RiskHRR=23.7%; P=0.08HRR=29.8%; P=0.03TOWER2TEMSO112-WeekConfirmedDisabilityProgression(%)0 12 24 36 48 60 72 84 96 108 120 132010203040Weeks21.022.215.8HRR=4.5%; P=0.76HRR=31.5%; P=0.04PlaceboTeriflunomide 7 mgTeriflunomide 14 mgPlaceboTeri 7 mgTerif14 mg388406370354375340325337310295314286271286267241248245195202211156163162128114124837787Number of Patients at Risk576163333840
42.348.637.80102030405060TENERE Outcomes25Annualized Relapse RateTreatment FailureSC IFNβ-1a Teriflunomide7 mgTeriflunomide14 mgPatients(%)n=104 n=109 n=1110.220.410.2600.050.10.150.188.8.131.520.40.45SC IFNβ-1a Teriflunomide7 mgTeriflunomide14 mgAdjusted*AnnualizedRelapseRate n=104 n=109 n=111*Adjusted annualized relapse rate, confirmed relapse.TENERE=Teriflunomide and Rebif® in Patients with RMS; SC=subcutaneous; IFNβ=interferon beta.Vermersch P et al. Presented at ENS; June 9–12, 2012; Prague, Czech Republic.P=0.03
Teriflunomide: Overview of Adverse Events andSerious Adverse Events27Proportionof Patients (%)TEMSO TOWERPlacebo(n=363)Teri7 mg(n=368)Teri14 mg(n=358)Placebo(n=385)Teri7 mg(n=409)Teri14 mg(n=371)Any adverse event 87.5 89.1 90.8 83.1 84.1 86.3Serious adverse events 12.8 14.1 15.9 12.2 12.7 11.9Deaths 0 0 0 0.3 0.2 0.5Adverse events leading totreatment discontinuation8.1 9.8 10.9 6.2 13.0 15.6O’Connor PW et al. N Engl J Med. 2011;365:1293-1303;Kappos L et al. MS Presented at ECTRIMS; October 10−13, 2012; Lyon, France. P153.
TEMSO: Safety and Tolerability*(Adverse Events with Incidence ≥10% in Any Group)Adverse Events, %Placebo(n=360)Teriflunomide 7 mg(n=368)Teriflunomide 14 mg(n=358)Any class 87.5 89.1 90.8Nasopharyngitis 27.2 25.5 26.0Headache† 17.8 22.0 18.7Diarrhea† 8.9 14.7 17.9Fatigue 14.2 12.8 14.5Elevated ALT† 6.7 12.0 14.2Nausea† 7.2 9.0 13.7Hair thinning, decreasedhair density†3.3 10.3 13.1Influenza 10.0 9.2 12.0Back pain 13.1 10.6 11.5Urinary tract infection 9.7 7.3 10.3Pain in arms or legs‡ 13.1 7.1 9.228*Events are displayed in order of decreasing incidence in the teriflunomide 14 mg group; †adverse events occurring at a higher rate in theteriflunomide group; ‡adverse events occurring at a higher rate in the placebo group.ALT=alanine aminotransferase.O’Connor PW et al. N Engl J Med. 2011;365:1293-1303.Difference in incidence of ≥3% between teriflunomide and placebo.
Teriflunomide: Common Adverse Events29Adverse Event, %TEMSO TOWERPlacebo(n=360)Teri7 mg(n=368)Teri14 mg(n=358)Placebo(n=385)Teri7 mg(n=409)Teri14 mg(n=371)Diarrhea 8.9 14.7 17.9 7.3 12.0 11.1Nausea 7.2 9.0 13.7 8.8 8.3 10.2Elevated ALT 6.7 12.0 14.2 8.3 11.2 14.0Hair thinning/decreased hair density3.3 10.3 13.1 4.4 10.3 13.5Hypersensitivity or skindisorders7.2 10.3 11.2 Not ReportedO’Connor PW et al. N Engl J Med. 2011;365:1293-1303;Kappos L et al. MS Presented at ECTRIMS; October 10−13, 2012; Lyon, France. P153.
TEMSO: Pregnancy Concerns▪ Pregnancy was reported as an adverse event, and 11 pregnancies occurredduring the study1- 4 spontaneous abortions (1 in placebo and 3 in teriflunomide 14 mg group)- 6 induced abortions (5 in teriflunomide 7 mg and 1 in teriflunomide 14 mg)- 1 patient in the teriflunomide 14 mg group delivered a healthy baby1▪ Patients who withdrew from the study for any reason or who did notparticipate in the extension study underwent an 11-day elimination period,during which they received cholestyramine or activated charcoal1▪ If a pregnancy is planned, plasma levels of teriflunomide have to be <0.02mg/L in 2 separate tests 14 days apart2▪ Without cholestyramine, half-lives (t½) of up to 96 days have been found(population kinetics analysis). For full safety in the worst case scenario, anestimated 11×t½, or approximately 2 years, would be needed to reach aplasma level of <0.02 mg/L3301. O’Connor MD et al. N Engl J Med. 2011;365:1293-1303; 2. Claussen MC et al. Clin Immunol. 2012;142:49-56;3. Aubagio (teriflunomide) [prescribing information]. Cambridge, MA: Genzyme Corporation; 2012.