Treating MS patients earlier in the disease progression may affect long-term outcomes 1-4 M S F O E S R U DISABILITY INCREASE O C L A R U T A N T N E M T A E R T R E T A L T N E M T A E R T Y L R A E TIME DISEASE ONSET The disease activity of MS should be treated as effectively as possible during the full duration of therapy, and particularly in the early course of disease 1 1
Introducing oral TECFIDERA: Strong efficacy for first-line treatment of RRMS Safety and efficacy demonstrated in two pivotal phase III trials in RRMS, DEFINE and CONFIRM, including over 2600 patients 5,6 • Two phase III trials, including one with an active comparator arm, were conducted in order to meet approval requirements from regulatory authorities • DEFINE: 2-year, randomised, double-blind, placebo-controlled phase III study in 1234 patients with RRMS • CONFIRM: 2-year, randomised, double-blind, placebo-controlled phase III study in 1417 patients with RRMS, including glatiramer acetate as a reference comparator 2
In the DEFINE study TECFIDERA reduced the number of relapses by approximately 50% in RRMS • In the primary endpoint measurement, TECFIDERA reduced the proportion of RRMS patients who relapsed by 49% 5 As shown by ARR, significant reductions vs placebo at 2 years 5 DEFINE Study 0.5 P <0.001 OVERALL POPULATION* 0.4 IN DEFINE STUDY 0.36 0.3 ARR 53 % ARR The annualised relapse rate (ARR) in each REDUCTION 0.2 treatment group was calculated as the total number of relapses experienced in a group 0.17 divided by the total number of subject-years 0.1 on study at 2 years (minus the time on alternative MS medication) for that group. 0.0 Placebo TECFIDERA (n=408) 240 mg BID (n=410) DEFINE: 2-year multicentre, randomised, double-blind, placebo-controlled study in 1234 patients with RRMS. 5 BID=twice a day. * Treatment-naive and previously treated patients. 3
In the DEFINE study TECFIDERA delayed physical disability progression As shown by EDSS, significant delay in disability progression vs placebo over 2 years 5 DEFINE Study 0.3 Placebo (n=408) 0.27 TECFIDERA 240 mg BID (n=410) OVERALL POPULATION* HR=0.62 Proportion of Patients With Confirmed Progression 95% CI (0.44, 0.87) IN DEFINE STUDY P =0.005 0.2 REDUCTION 38 % 0.16 IN DISABILITY PROGRESSION 0.1 0.0 24 48 72 96 Weeks DEFINE: 2-year multicentre, randomised, double-blind, placebo-controlled study in 1234 patients with RRMS. 5 CI=confidence interval, EDSS=Expanded Disability Status Scale, HR=hazard ratio. * Treatment-naive and previously treated patients. 4
In the rater-blinded, reference comparator CONFIRM study TECFIDERA reduced ARR in RRMS As shown by ARR, significant reductions vs placebo at 2 years 6 CONFIRM Study 0.5 0.5 OVERALL POPULATION* IN CONFIRM STUDY 0.4 0.4 0.40 0.40 29 % 44 % 0.3 0.3 ARR REDUCTION ARR ARR 0.29 0.2 0.2 0.22 0.1 0.1 P =0.01 P <0.001 0.0 0.0 Placebo Glatiramer acetate Placebo TECFIDERA (n=363) SC 20 mg QD (n=363) 240 mg BID (n=350) (n=359) CONFIRM: 2-year multicentre, randomised, double-blind, placebo-controlled study in 1417 patients with RRMS. 6 BID=twice a day QD=once a day. * Treatment-naive and previously treated patients. 5
Physical disability progression with TECFIDERA As shown by EDSS, delay in disability progression vs placebo over 2 years 5,6 DEFINE Study CONFIRM Study HR=0.62 HR=0.79 DEFINE AND CONFIRM STUDIES 95% CI (0.44, 0.87) 95% CI (0.52-1.19) 0.3 0.3 OVERALL POPULATION* IN P =0.005 P =0.25 0.27 Proportion of Patients With Proportion of Patients With Confirmed Progression Confirmed Progression 0.2 38 % 0.2 REDUCTION IN DISABILITY PROGRESSION 21 % REDUCTION 0.17 IN DISABILITY 0.16 PROGRESSION (NOT SIGNIFICANT) 0.13 0.1 0.1 0.0 0.0 Placebo TECFIDERA Placebo TECFIDERA (n=408) 240 mg BID (n=363) 240 mg BID (n=410) (n=359) DEFINE: 2-year multicentre, randomised, double-blind, placebo-controlled study in 1234 patients with RRMS. 5 CONFIRM: 2-year multicentre, randomised, double-blind, placebo-controlled study in 1417 patients with RRMS. 6 BID=twice a day * Treatment-naive and previously treated patients. 27% AND 17% OF PLACEBO-TREATED PATIENTS EXPERIENCED DISABILITY PROGRESSION IN THE DEFINE AND CONFIRM STUDIES, RESPECTIVELY 5,6 6
In the DEFINE study TECFIDERA reduced ARR in treatment-naive patients Treatment-naive patients: significant reduction in ARR vs placebo at 2 years 7 DEFINE Study 0.3 TREATMENT-NAIVE PATIENTS* P <0.05 46% OF BID PATIENTS 0.26 IN DEFINE HAD NOT IN DEFINE STUDY 0.2 RECEIVED ANY PRIOR ARR MS MEDICATION 67 % ARR REDUCTION 0.1 0.09 DEFINE: 2-year multicentre, randomised, double-blind, placebo-controlled study in 1234 patients with RRMS. 5 0.0 Placebo TECFIDERA (n= 181) 240 mg BID (n=187) * Had not received prior medication for the treatment of MS. 7
In the DEFINE study TECFIDERA delayed physical disability progression in treatment-naive patients As shown by EDSS, significant reduction in 12-week disability progression vs placebo at 2 years 7 DEFINE Study 0.3 P <0.05 TREATMENT-NAIVE PATIENTS* 0.28 46% OF BID PATIENTS Proportion of Patients With Confirmed Progression IN DEFINE HAD NOT IN DEFINE STUDY 0.2 RECEIVED ANY PRIOR REDUCTION 6 2 % MS MEDICATION IN DISABILITY PROGRESSION 0.12 0.1 DEFINE: 2-year multicentre, randomised, double-blind, placebo-controlled study in 1234 patients with RRMS. 5 0.0 Placebo TECFIDERA (n= 181) 240 mg BID (n=187) * Had not received prior medication for the treatment of MS. 8
In the DEFINE study TECFIDERA reduced MRI activity Significant reductions vs placebo in incidences of Gd+ lesions, new or newly enlarging T2 lesions, and new T1 hypointense lesions at 2 years 5,8 DEFINE Study Gd + T2 T1 P <0.001 P <0.001 P <0.0001 1.8 10 20 1.8 Mean Number of Gd+ Lesions Newly Enlarging T2 Lesions 1.5 17.0 Mean Number of New or 8 T1 Hypointense Lesions Mean Number of New 15 1.2 6 8 5 % 72 % 5.7 0.9 10 RELATIVE 4 90 % RELATIVE REDUCTION 0.6 REDUCTION OF NEW OF NEW OR NEWLY 5 T1 LESIONS RELATIVE ODDS ENLARGING 2 REDUCTION 0.3 T2 LESIONS 2.0 OF GD+ LESIONS 2.6 AT 2 YEARS 0.1 0.0 0 0 Placebo TECFIDERA Placebo TECFIDERA Placebo TECFIDERA ( n=165 ) (n= 1 65) 240 mg BID 240 mg BID (n=165) 240 mg BID (n=152) (n=152) (n=152) DEFINE: 2-year multicentre, randomised, double-blind, placebo-controlled study in 1234 patients with RRMS. 5 In the CONFIRM study • Patients experienced consistent, statistically significant reductions in the incidence of MRI-confirmed lesions 6 • TECFIDERA reduced the number of Gd+ lesions by 74%, T2 lesions by 71%, and T1 lesions by 57% vs placebo at 2 years ( P <0.0001) 6 9
In the DEFINE study TECFIDERA: strong efficacy for first-line treatment of RRMS ARR MRI EDSS Gd+ * T2 * T1 † 53 % 90 85 72 38 % % % % Proven Reduced Delayed reduction in brain lesions in progression relapse rates a broad range of of physical at 2 years 5 MRI measures 5,8 disability 5 ( P <0.001) *( P <0.001) † ( P <0.0001) ( P =0.005) TECFIDERA: a combination of strong efficacy and treatment simplicity for first-line treatment in RRMS patients 10
DEFINE: Change in Whole Brain Volume 9 Baseline to Year 2 Week 24 to Year 2 0.0 0 Median % Change in -0.2 Whole Brain Volume -0.4 − 0.46 − 0.55 − 0.64 -0.6 − 0.66 − 0.77 − 0.81 -0.8 17% 30% * NS 21% * -1.0 5% Placebo (n=163) NS BG-12 240 mg BID (n=151) BG-12 240 mg TID (n=152) P< – 5 11
CONFIRM: Change in Whole Brain Volume 10 Change from Baseline to Year 2 Change from Week 24 to Year 2 Median % Change in Whole Brain Volume 0.0 -0.2 -0.4 -0.640 -0.6 -0.660 -0.720 -0.745 -0.750 -0.765 -0.8 -0.945 -0.960 -1.0 5% 30% P =0.8306 P =0.0645 2% -1.2 21% P =0.5621 P =0.2636 2% 16% P =0.7063 P =0.8802 Placebo (n=144) BG-12 240 mg BID (n=147) BG-12 240 mg TID (n=143) GA (n=161) 6 12
ENDORSE Post Marketing ongoing study ENDORSE Efficacy: Time to First Relapse – Efficacy: Time to First Relapse DEFINE, CONFIRM, and ENDORSE Integrated Analysis DEFINE, CONFIRM, and ENDORSE Integrated Analysis (ITT Population) 13 (ITT Population) DEFINE and CONFIRM ENDORSE Proportion Relapsed 0.6 PBO/DMF TID at 4 Years PBO/DMF BID 0.496 0.5 GA/DMF TID 0.487 Probability of Relapse GA/DMF BID 0.432 DMF TID/DMF TID 0.409 0.4 0.380 DMF BID/DMF BID 0.362 0.3 0.2 0.1 0 Baseline 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 Time on Study (weeks) Patients at Risk DMF BID/DMF BID 501 469 445 430 417 401 393 379 367 352 339 335 326 319 307 297 272 502 464 443 423 410 405 392 387 382 363 348 335 322 307 292 282 260 DMF TID/DMF TID 249 229 212 192 179 171 161 154 146 123 116 113 110 109 106 101 93 PBO/DMF BID 248 223 206 192 177 168 163 149 142 121 111 110 106 103 100 98 93 PBO/DMF TID 118 111 103 95 89 84 81 79 77 69 65 62 60 58 54 52 41 GA/DMF BID 118 106 102 94 89 88 86 80 77 61 55 53 51 50 48 46 41 GA/DMF TID Only objective relapses were included in the Kaplan-Meier estimate analysis; patients who did not experience a relapse prior to switching – 1 13
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