daclizumab selection slides ectrims 2012
TRANSCRIPT
![Page 1: Daclizumab Selection Slides ECTRIMS 2012](https://reader034.vdocuments.net/reader034/viewer/2022042515/55653a94d8b42a313f8b4f63/html5/thumbnails/1.jpg)
Primary Results of the SELECTION Trial of
Daclizumab HYP in Relapsing Multiple
Sclerosis
Gavin Giovannoni1, Ralf Gold2, Krzysztof Selmaj3,
Eva Havrdova4, Xavier Montalban5, Ernst-Wilhelm
Radue6, Dusan Stefoski7, Manjit McNeill8, Jitesh
Rana8, Jacob Elkins8, and Gilmore O’Neill8
1Queen Mary University of London, Barts and The London School of Medicine and Dentistry, London,
UK; 2St. Josef-Hospital/Ruhr-University Bochum, Bochum, Germany; 3Medical University of Lodz, Lodz,
Poland; 4Charles University in Prague, Prague, Czech Republic; 5Hospital Vall d'Hebron University,
Barcelona, Spain; 6University Hospital Basel, Basel, Switzerland. 7Rush University Medical Center,
Chicago, IL. USA; 8Biogen Idec, Cambridge, MA, USA
![Page 2: Daclizumab Selection Slides ECTRIMS 2012](https://reader034.vdocuments.net/reader034/viewer/2022042515/55653a94d8b42a313f8b4f63/html5/thumbnails/2.jpg)
Disclosures
• This study was supported by Biogen Idec and Abbott Biotherapeutics Corp.
• Gavin Giovannoni: Has received research grant support from Bayer Schering Healthcare, Biogen Idec, GW Pharma, Merck Serono, Merz, Novartis, Teva and sanofi-aventis. Dr Giovannoni has received personal compensation for participating on Advisory Boards in relation to clinical trial design, trial steering committees and data and safety monitoring committees from: Bayer Schering Healthcare, Biogen Idec, Eisai, Elan, Five Prime Therapeutics, Genzyme, Genentech, GSK, Ironwood Pharma, Merck Serono, Novartis, Pfizer, Roche, sanofi-aventis, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals.
• Ralf Gold: Has received speakers’ honoraria and research grant support from Bayer Schering Healthcare, Biogen Idec, Merck Serono, Merz, Novartis, Teva and sanofi-aventis. Dr Gold has received compensation for Advisory Board activities from Biogen Idec, Merck Serono, Novartis and TEVA
• Krzysztof Selmaj: Has received speaker’s honoraria from Novartis, Merck Serono, Gedeon Richter, ONO Pharma, and Biogen Idec. Dr Selmaj has received personal compensation for participation in Advisory Boards and steering committees from Biogen Idec, Roche, Genzyme, ONO Pharma, Merck Serono, and Novartis.
• Eva Havrdova: Has received speakers’ honoraria and research grant support from Bayer Schering Healthcare, Biogen Idec, Genzyme, Merck Serono, Novartis, and Teva. Dr Havrdova has received compensation for Advisory Board activities from Biogen Idec, Genzyme, Merck Serono, Novartis and TEVA.
• Xavier Montalban: Has received speaking honoraria and travel expenses for speaking and scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, sanofi-aventis, Teva Pharmaceuticals, Almirall and BTG.
• Ernst-Wilhelm Radue: Has received research support (mainly for MS projects) and lecture fees from: Actelion, Basilea, Bayer Schering, Biogen Idec, Merck Serono, Novartis and others. Lecture fees have been mainly used for research funding at the Medical Image Analysis Center (former MS MRI Evaluation Center), University Hospital Basel
• Dusan Stefoski: Has received research funding and support, and speaker bureau honoraria from: Biogen Idec, EMD Serono, Teva, Pfizer, Elan, and Novartis.
• Randy Robinson: Full-time employee of Abbott Biotherapeutics.
• Manjit McNeill, Jitesh Rana, Jacob Elkins, and Gilmore O’Neill: Full-time employees of Biogen Idec.
2
![Page 3: Daclizumab Selection Slides ECTRIMS 2012](https://reader034.vdocuments.net/reader034/viewer/2022042515/55653a94d8b42a313f8b4f63/html5/thumbnails/3.jpg)
Hypothesized Immunomodulatory
Effect of Daclizumab Treatment
3 1. Bielekova B, et al. Proc Natl Acad Sci USA 2006;103: 5941–5946. 2. Martin J, et al. J Immunol 2010;185:1311–1320.
![Page 4: Daclizumab Selection Slides ECTRIMS 2012](https://reader034.vdocuments.net/reader034/viewer/2022042515/55653a94d8b42a313f8b4f63/html5/thumbnails/4.jpg)
Study design of SELECT and SELECTION
SELECT: n=621 SELECTION: n=517
Placebo
DAC HYP 150mg SC every 4 weeks
DAC HYP 300mg SC every 4 Weeks
Year 1
DAC HYP 150mg
DAC HYP 300mg
DAC HYP 150mg
DAC HYP 300mg
DAC HYP 150mg
Year 2
DAC HYP 300mg 24wk wash out
24wk wash out
Double-blind Treatment
*
*
*
* Randomization
Continuous 2 y DAC HYP 150mg
First year of DAC HYP
treatment
Continuous 2 y DAC HYP 300mg
Washout/ Reinitiation
Washout/ Reinitiation
All DAC HYP treatments were subcutaneous (SC) injections every 4 weeks.
Year 1 Year 2 Baseline End of washout
![Page 5: Daclizumab Selection Slides ECTRIMS 2012](https://reader034.vdocuments.net/reader034/viewer/2022042515/55653a94d8b42a313f8b4f63/html5/thumbnails/5.jpg)
Three key objectives in SELECTION
1. Safety / Efficacy of DAC HYP in subjects initiating treatment
– How does MS activity in year 2 after starting DAC HYP compare to year 1 on
placebo?
2. Safety / Efficacy of DAC HYP in subjects treated continuously
for 2-years
– Are effects maintained in year 2 of treatment compared to year 1?
3. Impact of washout period
– Rebound disease activity?
– Safety/efficacy after treatment re-initiation
Placebo
DAC HYP 150mg SC every 4 weeks
DAC HYP 300mg SC every 4 Weeks
Year 1
DAC HYP 150mg
DAC HYP 300mg
DAC HYP 150mg
DAC HYP 300mg
DAC HYP 150mg
Year 2
DAC HYP 300mg 24wk wash out
24 wk wash out
![Page 6: Daclizumab Selection Slides ECTRIMS 2012](https://reader034.vdocuments.net/reader034/viewer/2022042515/55653a94d8b42a313f8b4f63/html5/thumbnails/6.jpg)
Accounting of subjects
Placebo + DAC HYP 150 mg
Placebo + DAC HYP 300 mg
DAC HYP 150 mg + Washout
DAC HYP 150 mg for 2 yrs
DAC HYP 300 mg + Washout
DAC HYP 300 mg for 2 yrs
TOTAL
Number randomized in SELECTION
86 84
86
86
88
87
517
Percent of subjects who completed study treatment
89% 95% 86% 88% 88% 84% 88%
Percent of subjects who completed 1 year treatment phase
92% 95% 89% 91% 92% 89% 91%
![Page 7: Daclizumab Selection Slides ECTRIMS 2012](https://reader034.vdocuments.net/reader034/viewer/2022042515/55653a94d8b42a313f8b4f63/html5/thumbnails/7.jpg)
Efficacy of DAC HYP in Subjects
Initiating Treatment
7
SELECT SELECTION
Placebo
DAC HYP 150mg SC every 4 weeks
DAC HYP 300mg SC every 4 Weeks
Weeks 0-52
DAC HYP 150mg SC every 4 weeks
DAC HYP 300mg SC every 4 weeks
DAC HYP 150mg
DAC HYP 300mg
DAC HYP 150mg
Weeks 0-52
DAC HYP 300mg Wash Out
Wash Out
![Page 8: Daclizumab Selection Slides ECTRIMS 2012](https://reader034.vdocuments.net/reader034/viewer/2022042515/55653a94d8b42a313f8b4f63/html5/thumbnails/8.jpg)
Reduced annualized relapse rate
after initiation of DAC HYP
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
0.45
0.5
ARR=0.434 (0.347,0. 544)
ARR=0.179 (0.123, 0.261)
ARR Reduction = 59%
P<0.001
Placebo (Year 1)
n=163
DAC HYP (Year 2)
n=163
An
nu
ali
ze
d r
ela
pse
ra
te
![Page 9: Daclizumab Selection Slides ECTRIMS 2012](https://reader034.vdocuments.net/reader034/viewer/2022042515/55653a94d8b42a313f8b4f63/html5/thumbnails/9.jpg)
Reduced confirmed 3-month disability progression
after initiation of DAC HYP
10%
5%
0%
2%
4%
6%
8%
10%
12%
Reduction = 50% P = 0.033
17 subjects
with progression
Year 1 Year 2
7 subjects
with progression
Placebo
n=163
DAC HYP
n=163
Pe
rce
nt
of
pati
en
ts w
ith
co
nfi
rme
d
dis
ab
ilit
y p
rog
res
sio
n
![Page 10: Daclizumab Selection Slides ECTRIMS 2012](https://reader034.vdocuments.net/reader034/viewer/2022042515/55653a94d8b42a313f8b4f63/html5/thumbnails/10.jpg)
Reduced number of new MRI lesions
after initiation of DAC HYP
0
1
2
3
4
5
6
7
8
9
1.4 (2.4)
2.1 (3.7)
8.0 (9.5)
Reduction in
new or
newly enlarging
T2 Lesions
Reduction in
Gd+ Lesions
0.2 (0.8)
= 74%
= 86%
Year 1 Year 2 Year 1 Year 2 Placebo
n=162
DAC HYP
n=156
Placebo
n=163
DAC HYP
n=163
Nu
mb
er
of
new
MR
I le
sio
ns
(m
ea
n)
New/enlarging T2 lesions New Gd+ T1 lesions
![Page 11: Daclizumab Selection Slides ECTRIMS 2012](https://reader034.vdocuments.net/reader034/viewer/2022042515/55653a94d8b42a313f8b4f63/html5/thumbnails/11.jpg)
Efficacy of DAC HYP in Subjects
Treated Continuously for 2 years
11
SELECT SELECTION
DAC HYP 150mg SC every 4 weeks
DAC HYP 300mg SC every 4 weeks
Weeks 0-52 Weeks 0-52
DAC HYP 300mg SC every 4 weeks
DAC HYP 150mg SC every 4 weeks
![Page 12: Daclizumab Selection Slides ECTRIMS 2012](https://reader034.vdocuments.net/reader034/viewer/2022042515/55653a94d8b42a313f8b4f63/html5/thumbnails/12.jpg)
Reduction in ARR was sustained during
year 2 of DAC HYP treatment
12
0.434 (0.347, 0.544)
Year 2 of DAC HYP
62% reduction vs.
SELECT pbo
Year 1 of DAC HYP
66% reduction vs.
SELECT pbo
0.148 (0.096, 0.229)
Placebo
n=163
Year 1 Year 1 Year 2 DAC HYP
n=129
DAC HYP
n=129
An
nu
ali
ze
d R
ela
pse
Rate
![Page 13: Daclizumab Selection Slides ECTRIMS 2012](https://reader034.vdocuments.net/reader034/viewer/2022042515/55653a94d8b42a313f8b4f63/html5/thumbnails/13.jpg)
Low rate (12%) of confirmed disability
progression over 2 years of DAC HYP treatment
0.0
0.1
0.2
0.3
DAC HYP continuous
0 12 2463 9 15 18 21
DAC HYP Placebo
Placebo
6%
13%
50% risk reduction(95% CI, 12-71%; P=0.015)
Time on study (months)
Pro
po
rtio
n o
f p
ati
en
ts w
ith
co
nfi
rmed
dis
ab
ilit
y p
rog
ressio
n
![Page 14: Daclizumab Selection Slides ECTRIMS 2012](https://reader034.vdocuments.net/reader034/viewer/2022042515/55653a94d8b42a313f8b4f63/html5/thumbnails/14.jpg)
0.0
0.1
0.2
0.3
DAC HYP continuous
0 12 2463 9 15 18 21
DAC HYP
Placebo
Placebo
16%
12%
DAC HYP
DAC HYP after placebo
6%
13%
Placebo patients startDAC HYP
Time on study (months)
Pro
po
rtio
n o
f p
ati
en
ts w
ith
co
nfi
rmed
dis
ab
ilit
y p
rog
ressio
nLow rate (12%) of confirmed disability
progression over 2 years of DAC HYP treatment
![Page 15: Daclizumab Selection Slides ECTRIMS 2012](https://reader034.vdocuments.net/reader034/viewer/2022042515/55653a94d8b42a313f8b4f63/html5/thumbnails/15.jpg)
Reduction in new/newly enlarging T2 lesions was
stronger during year 2 of DAC HYP treatment
0
1
2
3
4
5
6
7
8
9
2.0 (4.0) 1.7 (3.6)
1.4(5.3)
1.0 (3.1)
8.2 (9.3)
Year 1
76% reduction
vs. SELECT pbo
Year 2
83% reduction
vs. SELECT pbo
Year 1
79% reduction
vs. SELECT pbo
Year 2
88% reduction
vs. SELECT pbo
Fewer new T2 lesions in Year 2 vs.
Year 1 of DAC HYP (P=0.032)
DAC HYP 150 mg
Year 1 n=195
Year 1 n=64
Year 2 n=63
Year 1 n=64
Year 2 n=65
Placebo DAC HYP 300 mg
Nu
mb
er
new
T2 l
es
ion
s (
mea
n)
![Page 16: Daclizumab Selection Slides ECTRIMS 2012](https://reader034.vdocuments.net/reader034/viewer/2022042515/55653a94d8b42a313f8b4f63/html5/thumbnails/16.jpg)
Impact of Washout / Re-initiation
of DAC HYP
16
SELECT SELECTION
DAC HYP 150mg SC every 4 weeks
DAC HYP 300mg SC every 4 weeks
Weeks 0-52 Weeks 0-52
DAC HYP 150mg Washout
DAC HYP 300mg Washout
![Page 17: Daclizumab Selection Slides ECTRIMS 2012](https://reader034.vdocuments.net/reader034/viewer/2022042515/55653a94d8b42a313f8b4f63/html5/thumbnails/17.jpg)
After 24-week washout from DAC HYP,
GD+ lesions were below pre-treatment baseline
1.9
1.2
0.5
0.2
0.4
0.2
1.2
0.9
0.2 0.2
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
Baseline
Wk 24
Wk 52
End of 24-wk washout
32-wks after restart
DAC HYP 300 mg DAC HYP 150 mg
End of 24 week washout
End of 24 week washout
Nu
mb
er
New
Gd
+ L
es
ion
s (
mea
n)
![Page 18: Daclizumab Selection Slides ECTRIMS 2012](https://reader034.vdocuments.net/reader034/viewer/2022042515/55653a94d8b42a313f8b4f63/html5/thumbnails/18.jpg)
Safety Results
18
![Page 19: Daclizumab Selection Slides ECTRIMS 2012](https://reader034.vdocuments.net/reader034/viewer/2022042515/55653a94d8b42a313f8b4f63/html5/thumbnails/19.jpg)
Adverse event summary
DAC HYP
150 mg
(n=86)
DAC HYP
300 mg
(n=84)
DAC HYP
150 mg
(n=86)
DAC HYP
300 mg
(n=87)
DAC HYP
150 mg
(n=86)
DAC HYP
300 mg
(n=88)
Any adverse event 71% 68% 66% 71% 81% 69%
Any serious
adverse event 15 (17) 11 (13) 15 (17) 11 (13) 18 (21) 15 (17)
Any serious
adverse event
excluding MS
relapse
7 (8) 4 (5) 6 (7) 7 (8) 6 (7) 4 (5)
Death, n 0 0 0 0 0 1*
19
* One patient died due to autoimmune hepatitis prior to implementation of hepatic
monitoring rules
DAC HYP Starters
Year 1 of DAC HYP DAC HYP Continuous
Year 2 of DAC HYP DAC HYP Washout /
Reinitiation
![Page 20: Daclizumab Selection Slides ECTRIMS 2012](https://reader034.vdocuments.net/reader034/viewer/2022042515/55653a94d8b42a313f8b4f63/html5/thumbnails/20.jpg)
Adverse events of interest
DAC HYP
150 mg
(n=86)
DAC HYP
300 mg
(n=84)
DAC HYP
150 mg
(n=86)
DAC HYP
300 mg
(n=87)
DAC HYP
150 mg
(n=86)
DAC HYP
300 mg
(n=88)
Serious Infections, n 3 1 2 2 3 2
Serious Cutaneous
Events, n 2 0 0 3 1 0
ALT/AST > 5x ULN, n 1 1 0 2 1 3
Other Serious
Immune-Mediated
Adverse Events, n 0 0 0 2 0 1
Malignancy, n 0 1 0 0 0 0
20
DAC HYP Starters
Year 1 of DAC HYP DAC HYP Continuous
Year 2 of DAC HYP DAC HYP Washout /
Reinitiation
![Page 21: Daclizumab Selection Slides ECTRIMS 2012](https://reader034.vdocuments.net/reader034/viewer/2022042515/55653a94d8b42a313f8b4f63/html5/thumbnails/21.jpg)
PD Results
21
![Page 22: Daclizumab Selection Slides ECTRIMS 2012](https://reader034.vdocuments.net/reader034/viewer/2022042515/55653a94d8b42a313f8b4f63/html5/thumbnails/22.jpg)
CD56bright NK cell counts plateaued during
second year of DAC HYP treatment
0
20
40
60
80
100
0 1 2 4 6 8 12 13 14 18 26
N=114
Time (months)
Me
dia
n (
25
-75
th p
erc
en
tile
s)
CD
56
bri
gh
t NK
ce
ll c
ou
nt
(ce
lls
/mm
3)
![Page 23: Daclizumab Selection Slides ECTRIMS 2012](https://reader034.vdocuments.net/reader034/viewer/2022042515/55653a94d8b42a313f8b4f63/html5/thumbnails/23.jpg)
Summary Evidence for high efficacy in subjects initiating DAC HYP
• 59% reduction in ARR after treatment start vs. year 1 pbo phase (p<0.001)
• 50% reduction in EDSS progression after treatment start vs. year 1 pbo phase (p=0.033)
Evidence for sustained efficacy in subjects continuing on DAC HYP for 2 years
• In subjects randomized to DAC HYP for 2 years
– ARR (0.15 in year 1; 0.17 in year 2)
– New T2 lesions at 52 weeks (1.9 in year 1 reduced to 1.2 in year 2, p=0.03)
No evidence for disease rebound during DAC washout
Pharmacodynamic changes plateau by second year of treatment
Safety profile was similar in year 2 compared to year 1
SELECTION vs. SELECT:
• Serious infections: 2% vs. 2%
• Serious cutaneous events: 1.1% vs. 1.0%
• New LFT abnormalities >5x ULN: 1.5% vs. 4%
No LFT elevations > 5x ULN or serious cutaneous events in year 2 of DAC 150mg
continuous group
![Page 24: Daclizumab Selection Slides ECTRIMS 2012](https://reader034.vdocuments.net/reader034/viewer/2022042515/55653a94d8b42a313f8b4f63/html5/thumbnails/24.jpg)
Acknowledgements
SELECTION Study Investigators
• Czech Republic: Prof. Zdeněk Ambler, Prof. Ivan Rektor, Dr. Radomir Talab, Prof. Petr Kanovsky, Dr. Pavel Stourac, Dr. Denisa Zimova, Dr. Marta Vachova
• Germany: Prof. Dr. Bernd C. Kieseier, Dr. Björn Tackenberg, Prof. Dr. Heinz Wiendl, Prof. Dr. Reinhard Hohlfeld, PD Dr. Klemens Angstwurm, Prof. Dr. Judith Haas, Prof. Dr. Uwe Zettl, Prof. Dr. Florian Stögbauer, Dr. Ralf Linker, Prof. Dr. Andrew Chan, Prof. Dr. Patrick Oschmann
• Hungary: Dr. Attila Csányi, Dr. Péter Diószeghy, Dr. János Nikl, Dr. Gyula Pánczel, Dr. Béla Clemens, Dr. Etelka Jófejű, Dr. Attila Valikovics, Dr. István Kondákor, Dr. Dániel Bereczki, Dr. Zsuzsanna Lohner, Prof. Lászlo Csiba, Dr. András Folyovich, Dr . Péter Harcos, Dr. Gabriella Kovács, Dr. Mária Sátori
• India: Dr. Rajaram Agarwal, Dr. Pahari Ghosh, Dr. Sangeeta Ravat, Dr. Subhash Mukherjee, Dr. Rustom Wadia, Prof. Kolichana Venkateswarlu, Dr. Meenakshisundaram Umaiorubahan, Prof. Medasari Padma, Dr. Thomas, Dr. A K Meena, Dr. Suresh Kumar
• Poland: Dr. Wieslaw Drozdowski, Dr. Waldemar Fryze, Dr. Jan Kochanowicz, Prof. Anna Kaminska, Dr. Krzysztof Selmaj, Dr. Andrzej Szczudlik, Dr. Andrzej Wajgt, Dr. Anna Czlonkowska, Dr. Zbigniew Stelmasiak, Dr. Gabriela Klodowska-Duda, Dr. Janusz Zbrojkiewicz
• Romania: Dr. Ovidiu Bajenaru, Dr. Dafin Fior Muresanu, Dr. Mihaela Simu
• Russia: Dr. Olga Vorobyeva, Dr. Leonid Zaslavsky, Dr. Sergey Shvarkov, Dr. Miroslav Odinak, Dr. Anna Belova, Dr. Irina Sokolova, Dr. Farit Khabirov, Dr. Natalia Nikolaevna Maslova, Dr. Irina Poverennova, Dr. Nikolay Spirin, Dr. Nadezhda Malkova, Dr. Semen Prokopenko, Dr. Alexey Rozhdestvensky, Dr. Alexei Boiko, Dr. Rim Magzhanov
• Turkey: Prof. Sabahattin Saip, Prof. Omer Faruk Turan, Ass. Prof. Serhat Ozkan, Prof. Ayse Sagduyu Kocaman
• Ukraine: Dr. Natalia Buchakchyys'ka, Dr. Natalia Lytvynenko, Dr. Borys Palamar, Dr. Tatyana Nehrych, Dr. Natalia Voloshina, Dr. Larisa Sokolova, Prof. Olexandr Kozyolkin, Dr. Olena Moroz, Prof. Valeriy Pashkovskyy, Dr. Elena Statinova, Dr. Tetjana Kobys, Dr. Igor Pasyura
• United Kingdom: Dr. Clive Hawkins, Dr. Basil Sharrack, Dr. Cris Constantinescu, Dr. John Zajicek, Dr. David Bates, Dr. Eli Silber
Data Safety Monitoring Board: Dr. Volker Limmroth (Chair), Dr. Richard Furie, Dr. Daniel McQuillen, Dr. Raymond Chung, Dr. Richard Kay
Relapse Adjudication Committee: Dr. Chris Polman, Dr. Ted Phillips, Dr. Paul O’Connor, Dr. Ari Green, Dr. Oliver Lyon-Caen
24 This study was supported by Biogen Idec and Abbott Biotherapeutics Corp.