Pooled dmf in newly diagnosed rrm sers giovannoni ens june 2013
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Pooled dmf in newly diagnosed rrm sers giovannoni ens june 2013

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  • 1. Effect of BG-12 (Dimethyl Fumarate) in NewlyDiagnosed Patients with Relapsing–Remitting MultipleSclerosis from the DEFINE and CONFIRM StudiesProf Gavin Giovannoni, MBBCh, PhD, FRCP, FRCPath10 June, 20131St Josef Hospital, Ruhr University, Bochum, Germany; 2Queen Mary University ofLondon, Blizard Institute, Barts and the London School of Medicine and Dentistry,London, UK; 3Multiple Sclerosis Program, Baylor Institute for Immunology Research,Dallas, TX, USA; 4Mellen Center for Multiple Sclerosis Treatment and Research,Cleveland Clinic, Cleveland, OH, USA; 5Biogen Idec Inc., Weston, MA, USAEuropean Neurological Society23rd Annual MeetingBarcelona, SpainGold R,1 Giovannoni G,2 Phillips JT,3 Fox RJ,4 Zhang A,5Meltzer L,5 Kurukulasuriya NC5
  • 2. Disclosures RG: honoraria from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis, andTeva Neuroscience; research support from Bayer HealthCare, Biogen Idec, MerckSerono, Novartis, and Teva Neuroscience GG: honoraria from Bayer HealthCare, Biogen Idec, Canbex, Genzyme,GlaxoSmithKline, Merck Serono, Novartis, Protein Discovery Laboratories, Roche,Synthon, Teva Neuroscience, and UCB; research support from Biogen Idec,Ironwood, Merck Serono, Merz, and Novartis; compensation from Elsevier as Co-Chief Editor of Multiple Sclerosis and Related Disorders JTP: honoraria from Acorda, Biogen Idec, Genzyme, Novartis, and Teva; researchsupport from Biogen Idec and Roche RJF: consultant fees from Allozyne, Avanir, Biogen Idec, Novartis, Questcor, andTeva; grant and research support from Novartis AZ, LM, NCK: employees of Biogen IdecSupported by Biogen Idec Inc.
  • 3.  Oral BG-12 (dimethyl fumarate) is approved in the United States for the treatment ofrelapsing forms of MS There is experimental evidence for anti-inflammatory and cytoprotective activity ofBG-12 via the Nrf2 transcriptional pathway BG-12 demonstrated significant efficacy on clinical and MRI measures in the Phase 3DEFINE and CONFIRM studies in patients with RRMS1,2- Efficacy was consistent across a broad range of pre-specified patient subgroups3 A pre-specified integrated analysis of DEFINE and CONFIRM was conducted toprovide a more precise estimate of the therapeutic effect of BG-12 relative to placebothan can be obtained from either study in isolationObjective To report a post hoc analysis of the efficacy of BG-12 in the newly diagnosed RRMSpatient population from the integrated DEFINE and CONFIRM data setIntroductionNrf2 = nuclear factor (erythroid-derived 2)-like 21. Gold R, et al. N Engl J Med 2012;367:1098−11072. Fox RJ, et al. N Engl J Med 2012;367:1087−10973. Bar-Or A, et al. Neurology 2013; 80(Meeting Abstracts 1):P07.095
  • 4. Study DesignYear 1 Year 20 48 968424 7212 36 60Study week:BG-12 240 mg TID POBG-12 240 mg BID POPlacebo POGlatiramer acetate (GA) 20 mg QD SC (reference comparator)Randomization1:1:1:1N=1,430BG-12 240 mg TID POBG-12 240 mg BID POPlacebo PORandomization1:1:1N=1,237CONFIRMDEFINEMRI cohorts:aDEFINE: n=540CONFIRM: n=681aSubset of patients from selected sites with MRI capabilities
  • 5. Key Inclusion and Exclusion Criteria Inclusion Criteria- Age 18–55 years- Diagnosis of RRMS (McDonald criteria 2005)- EDSS score of 0–5.0- ≥1 relapse in the 12 months prior to randomization or ≥1 Gd+ lesion(s)on brain MRI within 6 weeks prior to randomization Exclusion Criteria- Progressive forms of MS- Other significant illness or pre-specified abnormal laboratory parameters- A relapse or corticosteroids within 50 days prior to randomization- Prior treatment with GA• Within the past 3 months (DEFINE)• At any time (CONFIRM)
  • 6. Endpoints Primary endpoints- Proportion of patients relapsed at 2 years (primary endpoint in DEFINE)- Annualized relapse rate at 2 years (primary endpoint in CONFIRM) Additional endpoints at 2 years included- Twelve-week confirmed disability progression as measured by EDSS- Number of Gd+ lesions- Number of new/enlarging T2 hyperintense lesions- Number of new T1 hypointense lesions Clinical efficacy was assessed in the ITT population; MRIassessments were performed in the MRI cohort The integrated analysis plan was finalized prior to unblinding ofCONFIRM and was to be conducted only if baseline characteristicsand treatment effects were homogeneous across the studies
  • 7. Newly Diagnosed Population Newly diagnosed patients- Diagnosed with RRMS within a year from study entry- Had received no prior MS therapy (treatment naive) or had been treatedwith steroids only A total of 678 patients were newly diagnosed and were treated withBG-12 BID (n=221), BG-12 TID (n=234), or placebo (n=223)
  • 8. Baseline Characteristics(Newly Diagnosed Population)CharacteristicaPlacebo(n=223)BG-12 BID(n=221)BG-12 TID(n=234)Age, years 36.5 (9.4) 35.3 (9.4) 36.6 (9.6)Female, % 70 73 71Time since first MS symptoms, years 4.3 (5.3) 4.3 (5.8) 3.8 (4.1)Median (min, max) 2.0 (0, 31) 2.0 (0, 42) 2.0 (0, 23)Time since diagnosis, years 0.5 (0.5) 0.5 (0.5) 0.5 (0.5)Median (min, max) 1.0 (0, 1.0) 1.0 (0, 1.0) 1.0 (0, 1.0)Prior MS treatmentb naive, % 93 91 91Relapses in prior year 1.4 (0.6) 1.4 (0.6) 1.5 (0.6)McDonald criterion 1, % 75 68 69EDSS score 2.2 (1.1) 2.1 (1.1) 2.0 (1.0)Gd+ lesion volume,c cm3 0.2 (0.4) 0.3 (0.9) 0.1 (0.3)T2 lesion volume,c cm3 8.7 (10.9) 8.5 (9.0) 7.7 (10.7)T1 hypointense lesion volume,c cm3 2.0 (3.6) 2.2 (3.3) 1.6 (2.7)aValues are mean (SD) unless otherwise stated; bIncludes DMTs and non-DMTs; cMRI cohort only
  • 9. Annualized Relapse Rate at 2 Years0.380.17 0.15§56%§60%0.50.40.30.20.10Placebo(n=223)BG-12 BID(n=221)BG-12 TID(n=234)0.224AdjustedARR(95%CI)Rate ratios vs placebo (95% CI)BG-12 BID: 0.44 (0.30, 0.65)BG-12 TID: 0.40 (0.27, 0.58)§p<0.0001 vs placebo; ARR calculated with negative binomial regression, adjusted for baseline EDSS score(≤2.0 vs >2.0), baseline age (<40 vs ≥40), study, region, and number of relapses in the year prior to study entry
  • 10. Proportion of Patients Relapsed at 2 Years00.10.20.30.40.50.6BL 12 24 36 48 60 72 84 96Probabilityofrelapse0.422 (Placebo)Time on study (weeks)Hazard ratios vs placebo (95% CI)BG-12 BID: 0.46 (0.32, 0.67): 54% reduction; p<0.0001BG-12 TID: 0.43 (0.30, 0.62): 57% reduction; p<0.00010.213 (BG-12 BID)0.205 (BG-12 TID)223 198 178 161 144 132 125 115 108a221 190 170 158 151 147 143 141 131a234 199 190 176 170 166 156 151 140aProportionrelapsed at2 yearsPatients at riskPlaceboBG-12 BIDBG-12 TIDHazard ratios, 95% CI, and p-values based on a stratified Cox proportional hazards model with study as the stratifyingvariable, adjusted for baseline EDSS score (≤2.0 vs >2.0), baseline age (<40 vs ≥40), region, and number of relapses inthe year prior to study entry; aNumbers at risk 5 days prior to Week 96 (earlier window of Week 96 visit)
  • 11. Time to 12-Week Confirmed DisabilityProgression at 2 Years0.135 (BG-12 TID)00.10.20.30.4BL 12 24 36 48 60 72 84 960.233 (Placebo)Time on study (weeks)Hazard ratios vs placebo (95% CI)BG-12 BID: 0.29 (0.16, 0.53): 71% reduction; p<0.0001BG-12 TID: 0.53 (0.33, 0.85): 47% reduction; p=0.00850.073 (BG-12 BID)223 209 197 185 172 156 146 142 128a221 201 191 183 174 171 166 163 142a234 209 199 190 184 182 172 164 152aProportionprogressedat 2 yearsPatients at riskPlaceboBG-12 BIDBG-12 TIDHazard ratios, 95% CI, and p-values based on a stratified Cox proportional hazards model with study as the stratifyingvariable, adjusted for baseline EDSS score, baseline age (<40 vs ≥40), and region; aNumbers at risk 5 days prior toWeek 96 (earlier window of Week 96 visit)Probabilityofprogression
  • 12. Gd+ Lesions at 2 Years§p<0.0001 vs placebo, based on ordinal logistic regression, adjusted for study, region, and baseline number ofGd+ lesions; Percentages are the reduction in odds of having greater Gd+ lesion activity, compared with placebo1.90.3 0.2§92%§92%2.01.51.00.50Placebo(n=100)BG-12 BID(n=99)BG-12 TID(n=109)MeannumberoflesionsOdds ratios vs placebo (95% CI)BG-12 BID: 0.08 (0.03, 0.19)BG-12 TID: 0.08 (0.04, 0.20)
  • 13. New or Enlarging T2 Hyperintense Lesionsat 2 Years§p<0.0001 vs placebo, based on negative binomial regression, adjusted for study, region, and baseline volume ofT2 lesions20.04.0 3.9§80%§81%3020100Placebo(n=100)BG-12 BID(n=99)BG-12 TID(n=109)Adjustedmeannumberoflesions(95%CI)Lesion mean ratios vs placebo (95% CI)BG-12 BID: 0.20 (0.13, 0.31)BG-12 TID: 0.19 (0.13, 0.30)
  • 14. New T1 Hypointense Lesions at 2 Years§p<0.0001 vs placebo, based on negative binomial regression, adjusted for study, region, and baseline volume ofT1 lesions6.62.1 2.0§68%§70%1086420Placebo(n=100)BG-12 BID(n=99)BG-12 TID(n=109)Lesion mean ratios vs placebo (95% CI)BG-12 BID: 0.32 (0.21, 0.50)BG-12 TID: 0.30 (0.19, 0.46)Adjustedmeannumberoflesions(95%CI)
  • 15. Summary and Conclusions This post hoc analysis demonstrates that patients participating in thePhase 3 DEFINE and CONFIRM studies who are newly diagnosedwith RRMS derived clinical and neuroradiological benefit with BG-12treatment relative to placebo The findings in newly diagnosed patients mirror the results reportedfor the overall DEFINE and CONFIRM study populations evaluated inthe integrated analysis, supporting the consistent efficacy of BG-12 insubpopulations of patients from these studiesThe analyses suggest that treatment with BG-12 is consistentlyeffective across a broad range of patient subgroups, supporting itspotential to become a valuable oral treatment option for patients withrelapsing MSTogether with an acceptable safety profile in the overall studypopulations, this analysis supports BG-12 as a valuable oral treatmentoption for newly diagnosed RRMS patients