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

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

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.

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

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

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%

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

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

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

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

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

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

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

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

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)

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

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)

Safety Results

18

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

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

PD Results

21

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)

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

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.