Treating MS patients earlier in the disease progression may affect long-term outcomes 1-4

Size: px

Start display at page:

Download "Treating MS patients earlier in the disease progression may affect long-term outcomes 1-4"

Isabella Evans
5 years ago
Views:

1 Treating MS patients earlier in the disease progression may affect long-term outcomes 1-4 TIME DISEASE ONSET EARLY TREATMENT NATURAL COURSE OF MS LATER TREATMENT DISABILITY INCREASE 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,

approval requirements from regulatory authorities DEFINE: 2-year, randomised, double-blind, placebo-controlled phase III study in 1234 patients with RRMS

2 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

3 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 P<0.001 DEFINE Study OVERALL POPULATION* IN DEFINE STUDY ARR Placebo (n=408) 53% 0.17 TECFIDERA 240 mg BID (n=410) ARR REDUCTION The annualised relapse rate (ARR) in each treatment group was calculated as the total number of relapses experienced in a group divided by the total number of subject-years on study at 2 years (minus the time on alternative MS medication) for that group. 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

4 In the DEFINE study TECFIDERA delayed physical disability progression As shown by EDSS, significant delay in disability progression vs placebo over 2 years 5 Proportion of Patients With Confirmed Progression Placebo (n=408) TECFIDERA 240 mg BID (n=410) HR= % CI (0.44, 0.87) P= Weeks 38% DEFINE Study REDUCTION IN DISABILITY PROGRESSION OVERALL POPULATION* IN DEFINE STUDY 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

5 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 OVERALL POPULATION* IN CONFIRM STUDY ARR Placebo (n=363) 29% 0.29 P=0.01 Glatiramer acetate SC 20 mg QD (n=350) ARR Placebo (n=363) 44% 0.22 P<0.001 TECFIDERA 240 mg BID (n=359) ARR REDUCTION 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

6 Physical disability progression with TECFIDERA As shown by EDSS, delay in disability progression vs placebo over 2 years 5,6 DEFINE Study CONFIRM Study Proportion of Patients With Confirmed Progression Placebo (n=408) HR= % CI (0.44, 0.87) P=0.005 REDUCTION IN DISABILITY 38% PROGRESSION 0.16 TECFIDERA 240 mg BID (n=410) Proportion of Patients With Confirmed Progression Placebo (n=363) HR= % CI ( ) P= % REDUCTION IN DISABILITY PROGRESSION 0.13 (NOT SIGNIFICANT) TECFIDERA 240 mg BID (n=359) OVERALL POPULATION* IN DEFINE AND CONFIRM STUDIES 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

7 In the DEFINE study TECFIDERA reduced ARR in treatment-naive patients TREATMENT-NAIVE PATIENTS* IN DEFINE STUDY Treatment-naive patients: significant reduction in ARR vs placebo at 2 years 7 ARR P< Placebo (n=181) 67% 0.09 TECFIDERA 240 mg BID (n=187) ARR REDUCTION DEFINE Study 46% OF BID PATIENTS IN DEFINE HAD NOT RECEIVED ANY PRIOR MS MEDICATION DEFINE: 2-year multicentre, randomised, double-blind, placebo-controlled study in 1234 patients with RRMS. 5 * Had not received prior medication for the treatment of MS. 7

8 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 Proportion of Patients With Confirmed Progression P< Placebo (n=181) 62% 0.12 TECFIDERA 240 mg BID (n=187) REDUCTION IN DISABILITY PROGRESSION DEFINE Study 46% OF BID PATIENTS IN DEFINE HAD NOT RECEIVED ANY PRIOR MS MEDICATION DEFINE: 2-year multicentre, randomised, double-blind, placebo-controlled study in 1234 patients with RRMS. 5 TREATMENT-NAIVE PATIENTS* IN DEFINE STUDY * Had not received prior medication for the treatment of MS. 8

9 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 Gd+ T2 1.8 P<0.001 P< T1 DEFINE Study P< Mean Number of Gd+ Lesions Placebo (n=165) 90% RELATIVE ODDS REDUCTION OF GD+ LESIONS AT 2 YEARS 0.1 TECFIDERA 240 mg BID (n=152) Mean Number of New or Newly Enlarging T2 Lesions Placebo (n=165) 85% RELATIVE REDUCTION OF NEW OR NEWLY ENLARGING T2 LESIONS 2.6 TECFIDERA 240 mg BID (n=152) Mean Number of New T1 Hypointense Lesions Placebo (n=165) 72% RELATIVE REDUCTION OF NEW T1 LESIONS 2.0 TECFIDERA 240 mg BID (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

10 In the DEFINE study TECFIDERA: strong efficacy for first-line treatment of RRMS ARR 53 % Proven reduction in relapse rates at 2 years 5 Gd+* 90 % MRI T2* 85 % Reduced brain lesions in a broad range of MRI measures 5,8 T1 72 % EDSS 38 % Delayed progression of physical 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 0.0 Baseline to Year 2 Week 24 to Year 2 Median % Change in Whole Brain Volume -0.2-0.4-0.

11 DEFINE: Change in Whole Brain Volume Baseline to Year 2 Week 24 to Year 2 Median % Change in Whole Brain Volume %* % NS %* 5% NS Placebo (n=163) BG mg BID (n=151) BG mg TID (n=152) 11

CONFIRM: Change in Whole Brain Volume 10 Median % Change in Whole Brain Volume 0.0-0.2-0.4-0.6-0.8-1.0-1.2 Change from Baseline to Year 2 Change from Week 24 to Year 2-0.945-0.

12 CONFIRM: Change in Whole Brain Volume 10 Median % Change in Whole Brain Volume Change from Baseline to Year 2 Change from Week 24 to Year % P= % P= % P= % P= % P= % P= Placebo (n=144) BG mg BID (n=147) BG mg TID (n=143) GA (n=161) 12

13 ENDORSE Post Marketing ongoing study Efficacy: Time to First Relapse DEFINE, CONFIRM, and ENDORSE Integrated Analysis (ITT Population) 13 Probability of Relapse DEFINE and CONFIRM PBO/DMF TID PBO/DMF BID GA/DMF TID GA/DMF BID DMF TID/DMF TID DMF BID/DMF BID ENDORSE Proportion Relapsed at 4 Years Baseline 12 Patients at Risk Time on Study (weeks) DMF BID/DMF BID DMF TID/DMF TID PBO/DMF BID PBO/DMF TID GA/DMF BID GA/DMF TID Only objective relapses were included in the Kaplan-Meier estimate analysis; patients who did not experience a relapse prior to switching

14 ENDORSE Post Marketing ongoing study Efficacy: Time to Disability Progression by EDSS (24-Week Confirmation) DEFINE, CONFIRM, and ENDORSE Integrated Analysis (ITT Population) 14 Probability of Confirmed Disability Progression DEFINE and CONFIRM PBO/DMF TID PBO/DMF BID GA/DMF TID GA/DMF BID DMF TID/DMF TID DMF BID/DMF BID ENDORSE Proportion Progressed at 4 Years Baseline 12 Patients at Risk DMF BID/DMF BID DMF TID/DMF TID PBO/DMF BID PBO/DMF TID GA/DMF BID GA/DMF TID Time on Study (weeks)

15 TECFIDERA showed a manageable tolerability profile Gastrointestinal (GI) and flushing events were the most common adverse events 8 Adverse event* Placebo TECFIDERA 240 mg BID Diarrhoea 10% 14% Nausea 9% 12% Upper abdominal pain 6% 10% Abdominal pain 4% 9% Vomiting 5% 8% Dyspepsia 3% 5% Flushing 4% 34% * For other adverse events please see label. These events were mostly mild to moderate 8 GI and flushing events tended to begin early in the course of treatment (primarily in month 1) 8 For patients who experience these events, they may continue to occur intermittently throughout TECFIDERA treatment 15

16 Integrated Analysis: Incidence of Flushing Events* and Gastrointestinal Events by Study Month Patients (%) Patients (%) Flushing Events Placebo (n=408) BG mg BID (n=410) BG mg TID (n=416) Month Gastrointestinal Events Month *Flushing events include the preferred terms flushing, hot flush, erythema, generalized erythema, burning sensation, skin burning sensation, feeling hot, and hyperemia; gastrointestinal events include the preferred terms in the level 2 subordinate standardized MedDRA queries gastrointestinal nonspecific inflammations or gastrointestinal nonspecific symptoms and therapeutic procedures. BID=twice daily; TID=3 times daily. Selmaj K et al. Presented at ECTRIMS; October 10 13, 2012; Lyon, France. P

17 Measures designed to help minimize GI and flushing adverse events Measures to improve tolerability 8 GI Flushing Starting dose of 120 mg twice a day for 7 days Temporary dose reduction of TECFIDERA to 120 mg BID; within 1 month, the recommended dose of 240 mg BID orally should be resumed Taking with food Administration of 325-mg (or equivalent) non-enteric coated aspirin* prior to TECFIDERA dosing * Long-term use of aspirin is not recommended for the management of flushing. Potential risks associated with aspirin should be considered prior to co-administration with TECFIDERA. 8 17

18 DEFINE: Lymphocyte Counts Mean Lymphocyte Count ( 10 9 /L) Placebo BG mg BID BG mg TID LLN BL Visit (weeks) n=407 (baseline) to 245 (week 96) n=410 (baseline) to 271 (week 96) n=416 (baseline) to 268 (week 96) Hematology Parameters: Mean Values over Time Placebo BG mg BID BG mg TID Note: LLN is lower limit in standard unit; if multiple values were given for LLN of any parameter, the highest LLN is shown. DEFINE=Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS; BID=twice daily; TID=3 times daily; LLN=lower limit of normal; BL=baseline; MS=multiple sclerosis. Biogen Idec, data on file. 18

Flushing 3% THE INCIDENCE OF GI AND FLUSHING (THE MOST COMMON

19 Low discontinuation due to incidence of GI and flushing events Events leading to discontinuation 8 TECFIDERA 240 mg BID GI 4% Flushing 3% THE INCIDENCE OF GI AND FLUSHING (THE MOST COMMON ADVERSE EVENTS) LEADING TO DISCONTINUATION WAS GENERALLY LOW 8 19

20 TECFIDERA showed a favourable safety profile 8 The overall incidences of renal adverse reactions were similar for TECFIDERA and placebo There was a small difference between TECFIDERA BID (9%) and placebo (7%) for proteinuria Infection risk and serious infection rate with TECFIDERA were comparable with placebo No increased incidence of serious infections observed in patients with lymphocyte counts <0.8x10 9 /l or <0.5x10 9 /l Lymphocyte counts decreased by approximately 30% over the first year, then plateaued Mean and median lymphocyte counts remained within normal limits The long-term, clinical significance of these effects is not known. 20

21 In clinical trials, a total of 2468 patients have received TECFIDERA and been followed for periods up to 4 years with an overall exposure equivalent to 3588 person-years 8 Approximately 1056 patients have received more than 2 years of treatment with TECFIDERA The experience in uncontrolled clinical trials isconsistent with the experience in the placebocontrolled clinical trials 21

22 Monitoring requirements 8 Complete blood counts Hepatic function tests Every 6 to 12 months thereafter and as clinically indicated Renal function tests Month O AFTER 6 MONTHS, ASSESSMENTS CAN BE ACCOMPLISHED WITH A SINGLE BLOOD DRAW AND URINE SAMPLE AT 6- TO 12-MONTH INTERVALS AND AS CLINICALLY INDICATED 22

23 In the DEFINE study TECFIDERA: a new oral treatment for RRMS patients offering strong efficacy, manageable tolerability, and a favourable safety profile STRONG EFFICACY YOU WANT FOR FIRST-LINE TREATMENT 5 ARR Proven reduction in relapse rates at 2 years EDSS Delayed progression of physical disability MRI Reduced brain lesions in a broad range of MRI measures ARR 53 % (P<0.001) EDSS 38 % (P=0.005) Gd+ 90 % (P<0.001) REDUCTION IN RELAPSE RATES REDUCTION OF PHYSICAL DISABILITY T2 85 % (P<0.001) 23

24 SIMPLICITY THEY NEED FOR FIRST-LINE TREATMENT 7 SAFETY AND MONITORING Favourable safety profile with monitoring aligned with clinical practice TWICE-DAILY ORAL DOSING Day Night 24

25 TECFIDERA oral dosing Start with Continue with am 120 mg pm 120-mg capsules have a green cap and white body printed with BG mg in black ink on the body 8 am pm 240 mg 240-mg capsules have a green cap and a green body printed with BG mg in black ink on the body 8 Twice-daily TECFIDERA should be taken with food morning and evening 25

26 1. Gold R, Hartung H-P, Stangel M, Wiendl H, Zipp F. Therapeutic goals of platform and escalation therapies for relapsing-remitting multiple sclerosis. Akt Neurol. 2012;39: Leray E, Yaouang J, Le Page E, et al. Evidence for a two-stage disability progression in multiple sclerosis. Brain. 2010;133: Confavreux C, Vukusic S, Moreau T, Adeleine P. Relapses and progression of disability in multiple sclerosis. N Engl J Med. 2000;343(20): Confavreux C, Vukusic S, Adeleine P. Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process. Brain. 2003;126: Gold G, Kappos L, Arnold DL, et al; DEFINE Study Investigators. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367(12): Fox RJ, Miller DH, Phillips JT, et al; CONFIRM Study Investigators. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012;367(12): Bar-Or A, Gold R, Kappos L, et al. Effect of BG-12 in subgroups of patients with relapsing remitting multiple sclerosis: findings from the DEFINE study. Poster presented at: 64th Annual Meeting of the American Academy of Neurology; April 21-28, 2012, New Orleans; LA. P TECFIDERA Summary of Product Characteristics. Biogen Idec. 9. *P<0.05 vs placebo, based on ANCOVA on ranked data, adjusted for region and normalized brain volume at baseline/week 24. DEFINE=Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS; NS=not statistically significant vs placebo; BID=twice daily; TID=3 times daily; ANCOVA=analysis of covariance; MS=multiple sclerosis. Arnold DL et al. Presented at AAN; April 21 28, 2012; New Orleans, LA. S CONFIRM=Comparator and an Oral Fumarate in Relapsing-Remitting MS; BID=twice daily; TID=3 times daily; GA=glatiramer acetate; MS=multiple sclerosis. Biogen Idec, data on file. 11. Adjusted mean and 95% CI based on negative binomial regression, adjusted for region and baseline volume of T2 lesions at the start of DEFINE and CONFIRM; data after subjects switched to alternative MS medications were excluded. DMF, dimethyl fumarate. Miller DH, et al. Presented at: ECTRIMS, October 2 5, 2013, Copenhagen, Denmark. Poster P The MOGISS reflects the impact of GI-related events on the patient during the 24 hours prior to data entry. P Fox EJ et al, P2.227 AAN Only objective relapses were included in the Kaplan-Meier estimate analysis; patients who did not experience a relapse prior to switching to alternative MS medications or withdrawal from study were censored at the time of switch/withdrawal. *Two years in DEFINE/CONFIRM and 2 years in ENDORSE. DMF, dimethyl fumarate. Gold R, et al. Presented at: ECTRIMS, October 2 5, 2013, Copenhagen, Denmark. Poster P Subjects were censored if they withdrew from study or switched to alternative MS medication without a progression. DMF, dimethyl fumarate. Gold R, et al. Presented at: ECTRIMS, October 2 5, 2013, Copenhagen, Denmark. Poster P Dimethyl Fumarate: A review of its use in patients with Relapsing- Remitting Multiple Sclerosis Celeste B. Burness- Emma D. Decks CNS Drugs DOI /s published online: March 13th

Dimethyl Fumarate (Tecfidera) pathway for Walton Centre MS patients

Dimethyl Fumarate (Tecfidera) pathway for Walton Centre MS patients Author and Contact details: Responsible Director: Ian Pomeroy Service lead for MS. Tel: (0151) 529 5715 Email: ian.pomeroy@thewaltoncentre.nhs.uk