Treating MS patients earlier in the disease progression may affect - - PowerPoint PPT Presentation
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
1
Treating MS patients earlier in the disease progression may affect long-term outcomes1-4 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
DISABILITY INCREASE
DISEASE ONSET
N A T U R A L C O U R S E O F M S L A T E R T R E A T M E N T E A R L Y T R E A T M E N T
TIME
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 patients5,6
were conducted in order to meet approval requirements from regulatory authorities
study in 1234 patients with RRMS
phase III study in 1417 patients with RRMS, including glatiramer acetate as a reference comparator
3
As shown by ARR, significant reductions vs placebo at 2 years5
In the DEFINE study
TECFIDERA reduced the number of relapses by approximately 50% in RRMS
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
alternative MS medication) for that group.
0.5 0.4 0.3 ARR Placebo
(n=408)
P<0.001 TECFIDERA
240 mg BID (n=410)
0.2 0.1 0.0
0.36 0.17
ARR REDUCTION
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.
DEFINE Study OVERALL POPULATION* IN DEFINE STUDY
proportion of RRMS patients who relapsed by 49%5
4
DEFINE Study
As shown by EDSS, significant delay in disability progression vs placebo over 2 years5
In the DEFINE study
TECFIDERA delayed physical disability progression
HR=0.62 95% CI (0.44, 0.87)
P=0.005
0.27 0.16
Placebo (n=408) TECFIDERA 240 mg BID (n=410) Proportion of Patients With Confirmed Progression 0.3 0.2 0.1 0.0 48 72 24 96 Weeks
REDUCTION IN DISABILITY PROGRESSION
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.
OVERALL POPULATION* IN DEFINE STUDY
5
As shown by ARR, significant reductions vs placebo at 2 years6
In the rater-blinded, reference comparator CONFIRM study
TECFIDERA reduced ARR in RRMS
0.5 0.4 0.3 ARR 0.2 0.1 0.0
Glatiramer acetate
SC 20 mg QD (n=350)
P=0.01
0.29
Placebo
(n=363) 0.40
0.5 0.4 0.3 ARR Placebo
(n=363)
TECFIDERA
240 mg BID (n=359)
0.2 0.1 0.0 P<0.001
0.22 0.40
ARR REDUCTION
CONFIRM Study OVERALL POPULATION* IN CONFIRM STUDY
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.
6
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.
DEFINE Study CONFIRM Study OVERALL POPULATION* IN DEFINE AND CONFIRM STUDIES
As shown by EDSS, delay in disability progression vs placebo over 2 years5,6
Physical disability progression with TECFIDERA
0.3 Placebo
(n=408)
TECFIDERA
240 mg BID (n=410)
0.2 0.1 0.0
0.27 0.16
HR=0.62 95% CI (0.44, 0.87)
P=0.005 Proportion of Patients With Confirmed Progression 0.3 Placebo
(n=363)
TECFIDERA
240 mg BID (n=359)
0.2 0.1 0.0
0.17 0.13
Proportion of Patients With Confirmed Progression
HR=0.79 95% CI (0.52-1.19)
P=0.25
(NOT SIGNIFICANT) REDUCTION IN DISABILITY PROGRESSION
REDUCTION IN DISABILITY PROGRESSION
27% AND 17% OF PLACEBO-TREATED PATIENTS EXPERIENCED DISABILITY PROGRESSION IN THE DEFINE AND CONFIRM STUDIES, RESPECTIVELY5,6
7
Treatment-naive patients: significant reduction in ARR vs placebo at 2 years7
In the DEFINE study
TECFIDERA reduced ARR in treatment-naive patients
* Had not received prior medication for the treatment of MS.
0.3 ARR Placebo
(n=181)
P<0.05 TECFIDERA
240 mg BID (n=187)
0.2 0.1 0.0
0.26 0.09
ARR REDUCTION DEFINE: 2-year multicentre, randomised, double-blind, placebo-controlled study in 1234 patients with RRMS.5
DEFINE Study
46% OF BID PATIENTS IN DEFINE HAD NOT RECEIVED ANY PRIOR MS MEDICATION
TREATMENT-NAIVE PATIENTS* IN DEFINE STUDY
8
* Had not received prior medication for the treatment of MS.
As shown by EDSS, significant reduction in 12-week disability progression vs placebo at 2 years7
0.3 Placebo
(n=181)
P<0.05 TECFIDERA
240 mg BID (n=187)
0.2 0.1 0.0
0.28 0.12
REDUCTION IN DISABILITY PROGRESSION
Proportion of Patients With Confirmed Progression
In the DEFINE study
TECFIDERA delayed physical disability progression in treatment-naive patients
46% OF BID PATIENTS IN DEFINE HAD NOT RECEIVED ANY PRIOR MS MEDICATION
TREATMENT-NAIVE PATIENTS* IN DEFINE STUDY DEFINE Study
DEFINE: 2-year multicentre, randomised, double-blind, placebo-controlled study in 1234 patients with RRMS.5
9
Significant reductions vs placebo in incidences of Gd+ lesions, new or newly enlarging T2 lesions, and new T1 hypointense lesions at 2 years5,8
In the DEFINE study
TECFIDERA reduced MRI activity
In the CONFIRM study
incidence of MRI-confirmed lesions6
and T1 lesions by 57% vs placebo at 2 years (P<0.0001) 6
DEFINE: 2-year multicentre, randomised, double-blind, placebo-controlled study in 1234 patients with RRMS.5
RELATIVE REDUCTION OF NEW OR NEWLY ENLARGING T2 LESIONS
RELATIVE ODDS REDUCTION OF GD+ LESIONS AT 2 YEARS
RELATIVE REDUCTION OF NEW T1 LESIONS
1.8 1.5 Mean Number of Gd+ Lesions Placebo
(n=165)
P<0.001 TECFIDERA
240 mg BID (n=152)
1.2 0.9 0.6 0.3 0.0
10 8 Mean Number of New T1 Hypointense Lesions Placebo
(n=165)
P<0.0001 TECFIDERA
240 mg BID (n=152)
6 4 2
20 5 15 10 Mean Number of New or Newly Enlarging T2 Lesions Placebo (n=165) P<0.001 TECFIDERA
240 mg BID (n=152)
1.8 0.1 5.7 2.0 17.0 2.6
DEFINE Study
10
In the DEFINE study
TECFIDERA: strong efficacy for first-line treatment of RRMS TECFIDERA: a combination of strong efficacy and treatment simplicity for first-line treatment in RRMS patients
% Delayed progression
disability5
(P=0.005)
EDSS
% Proven reduction in relapse rates at 2 years5
(P<0.001)
ARR MRI
Reduced brain lesions in a broad range of MRI measures5,8
Gd+*
%
T2*
%
T1†
%
†(P<0.0001)
*(P<0.001)
11
DEFINE: Change in Whole Brain Volume9
−0.81 −0.66 −0.64 −0.46 −0.77 −0.55
0.0 Baseline to Year 2 Week 24 to Year 2
Placebo (n=163) BG-12 240 mg BID (n=151) BG-12 240 mg TID (n=152)
5
Median % Change in Whole Brain Volume
21%* 5% NS
P< –
30%* 17% NS
12
CONFIRM: Change in Whole Brain Volume10
6
0.0 Change from Baseline to Year 2 Change from Week 24 to Year 2
Placebo (n=144) BG-12 240 mg BID (n=147) BG-12 240 mg TID (n=143) GA (n=161)
Median % Change in Whole Brain Volume
30% P=0.0645 21% P=0.2636 2% P=0.8802 5% P=0.8306 2% P=0.5621 16% P=0.7063
13
1 Only objective relapses were included in the Kaplan-Meier estimate analysis; patients who did not experience a relapse prior to switching –
Time on Study (weeks) Probability of Relapse Proportion Relapsed at 4 Years 0.1 0.2 0.3 0.4 0.5 0.6 12
469 464 229 223 111 106
24
445 443 212 206 103 102
36
430 423 192 192 95 94
48
417 410 179 177 89 89
60
401 405 171 168 84 88
72
393 392 161 163 81 86
84
379 387 154 149 79 80
96
367 382 146 142 77 77
108
352 363 123 121 69 61
120
339 348 116 111 65 55
132
335 335 113 110 62 53
144
326 322 110 106 60 51
156
319 307 109 103 58 50
168
307 292 106 100 54 48
180
297 282 101 98 52 46
192
272 260 93 93 41 41
DEFINE and CONFIRM ENDORSE
0.496 0.487 0.432 0.409 0.380 0.362 Baseline
501 502 249 248 118 118 Patients at Risk DMF BID/DMF BID DMF TID/DMF TID PBO/DMF BID PBO/DMF TID GA/DMF BID GA/DMF TID
PBO/DMF TID PBO/DMF BID GA/DMF TID GA/DMF BID DMF TID/DMF TID DMF BID/DMF BID
ENDORSE Post Marketing ongoing study Efficacy: Time to First Relapse
DEFINE, CONFIRM, and ENDORSE Integrated Analysis (ITT Population)13
14
2 –
Probability of Confirmed Disability Progression 0.1 0.2 0.3 Baseline
501 502 249 248 118 118
12
469 464 229 223 111 106
24
445 443 212 206 103 102
36
430 423 192 192 95 94
48
417 410 179 177 89 89
60
401 405 171 168 84 88
72
393 392 161 163 81 86
84
379 387 154 149 79 80
96
367 382 146 142 77 77
108
352 363 123 121 69 61
120
339 348 116 111 65 55
132
335 335 113 110 62 53
144
326 322 110 106 60 51
156
319 307 109 103 58 50
180
297 282 101 98 52 46
192
272 260 93 93 41 41
0.231 0.214 0.199 0.168 0.164 0.154 Time on Study (weeks) 168
307 292 106 100 54 48 Patients at Risk DMF BID/DMF BID DMF TID/DMF TID PBO/DMF BID PBO/DMF TID GA/DMF BID GA/DMF TID
Proportion Progressed at 4 Years
DEFINE and CONFIRM ENDORSE
PBO/DMF TID PBO/DMF BID GA/DMF TID GA/DMF BID DMF TID/DMF TID DMF BID/DMF BID
ENDORSE Post Marketing ongoing study Efficacy: Time to Disability Progression by EDSS (24-Week Confirmation)
DEFINE, CONFIRM, and ENDORSE Integrated Analysis (ITT Population)14
15
TECFIDERA showed a manageable tolerability profile
(primarily in month 1)8 — For patients who experience these events, they may continue to occur intermittently throughout TECFIDERA treatment Gastrointestinal (GI) and flushing events were the most common adverse events8
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.
16
2
*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. P484.
Placebo (n=408) BG-12 240 mg BID (n=410) BG-12 240 mg TID (n=416) 10 5 25 30 35 20 15 1 2 3 4 5 6 7 8 9 10 11 12 24 Month Patients (%) 30 25 20 15 10 5 1 2 3 4 5 6 7 8 9 10 11 12 24 Month Patients (%) 35
Flushing Events Gastrointestinal Events
Integrated Analysis: Incidence of Flushing Events* and Gastrointestinal Events† by Study 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
17 * 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
Measures to improve tolerability8 GI Flushing Starting dose of 120 mg twice a day for 7 days
120 mg BID; within 1 month, the recommended dose of 240 mg BID orally should be resumed
coated aspirin* prior to TECFIDERA dosing
GI and flushing adverse events
18
1
0.5 1.0 1.5 2.0 2.5 3.0 Mean Lymphocyte Count (×109/L) BL 8 12 24 36 48 60 72 84 96 4
LLN
n=407 (baseline) to 245 (week 96) n=410 (baseline) to 271 (week 96) n=416 (baseline) to 268 (week 96)
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.
Placebo BG-12 240 mg BID BG-12 240 mg TID
Visit (weeks)
Hematology Parameters: Mean Values over Time Placebo BG-12 240 mg BID BG-12 240 mg TID
DEFINE: Lymphocyte Counts
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
BL=baseline; MS=multiple sclerosis. Biogen Idec, data on file.
19
Low discontinuation due to incidence of GI and flushing events
Events leading to discontinuation8 TECFIDERA
240 mg BID
GI 4% Flushing 3%
THE INCIDENCE OF GI AND FLUSHING (THE MOST COMMON ADVERSE EVENTS) LEADING TO DISCONTINUATION WAS GENERALLY LOW8
20
TECFIDERA showed a favourable safety profile8
for TECFIDERA and placebo — There was a small difference between TECFIDERA BID (9%) and placebo (7%) for proteinuria
comparable with placebo
lymphocyte counts <0.8x109/l or <0.5x109/l
first year, then plateaued — Mean and median lymphocyte counts remained within normal limits
The long-term, clinical significance of these effects is not known.
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-years8
isconsistent with the experience in the placebo- controlled clinical trials
22
Monitoring requirements8
Complete blood counts Every 6 to 12 months thereafter and as clinically indicated Hepatic function tests Renal function tests
Month O 2 1 3 4 5 6
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
23
In the DEFINE study
TECFIDERA: a new oral treatment for RRMS patients
a favourable safety profile
REDUCTION OF PHYSICAL DISABILITY
STRONG EFFICACY YOU WANT FOR FIRST-LINE TREATMENT5
REDUCTION IN RELAPSE RATES
(P<0.001)
T2
(P=0.005)
EDSS
(P<0.001)
ARR
(P<0.001)
Gd+
Proven reduction in relapse rates at 2 years Delayed progression of physical disability Reduced brain lesions in a broad range
24
SIMPLICITY THEY NEED FOR FIRST-LINE TREATMENT7
Favourable safety profile with monitoring aligned with clinical practice
Day Night
25
TECFIDERA oral dosing
120-mg capsules have a green cap and white body printed with “BG-12 120 mg” in black ink on the body8
Start with 120 mg
AM PM
Continue with 240 mg
240-mg capsules have a green cap and a green body printed with “BG-12 240 mg” in black ink on the body8
AM PM
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;39:342– 350. 2. Leray E, Yaouang J, Le Page E, et al. Evidence for a two-stage disability progression in multiple sclerosis. Brain. 2010;133:1900-1913. 3. Confavreux C, Vukusic S, Moreau T, Adeleine P. Relapses and progression of disability in multiple sclerosis. N Engl J Med. 2000;343(20):1430-1438. 4. Confavreux C, Vukusic S, Adeleine P. Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process. Brain. 2003;126:770- 782. 5. 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):1098-1107. 6. 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):1087-1097. 7. 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. P01.130.
data on file.
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 P1004.
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 P538.
ECTRIMS, October 2–5, 2013, Copenhagen, Denmark. Poster P538.
10.1007/s40263-014-0155-5 published online: March 13th 2014