The Safety and Efficacy of Daclizumab HYP in Relapsing-Remitting Multiple Sclerosis in the SELECTION Extension Study: Primary Results

Dr Gavin Giovannoni, MBBCh, PhD, FRCP, FRCPath

June 10, 2013

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

European Neurological Society

23rd Meeting

Barcelona, Spain

Disclosures

2

This study was supported by Biogen Idec and AbbVie Biotherapeutics.

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.

Manjit McNeill, Jitesh Rana, Jacob Elkins, and Gilmore O’Neill: Full-time employees of Biogen Idec.

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

4 All DAC HYP treatments were subcutaneous (SC) injections every 4 weeks.

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

Year 1 Year 2 Baseline End of washout

DAC HYP, daclizumab high-yield process

Three Key Objectives in SELECTION

5

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

6

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% 91% 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 1-year of DAC HYP

8

Year 1 Year 2 Placebo

n=163

DAC HYP

n=163

ARR Reduction = 59%

P<0.001

ARR=0.434 (0.347,0. 544)

ARR=0.179 (0.123, 0.261)

ARR, annualized relapse rate

Reduced Confirmed Disability Progression after

1-year of DAC HYP

9

Reduction = 54% P = 0.033

18 subjects

with progression

Year 1 Year 2

8 subjects

with progression

Placebo

n=163

DAC HYP

n=163

Pe

rce

nt

of

pa

tie

nts

wit

h

co

nfi

rme

d d

isa

bilit

y p

rog

res

sio

n

Sustained progression is defined as at least a 1.0 point increase on the EDSS from a SELECT baseline EDSS >= 1.0 sustained for 3 months or at least a 1.5 point increase on the EDSS from

a SELECT baseline EDSS of 0 sustained for 3 months. A cutoff of 74 days was used to determine sustained progression for 3 months.

Reduction in Number of New MRI Lesions

after 1-year of DAC HYP

10

1.4 (2.4)

2.1 (3.7)

8.0 (9.5)

0.2 (0.8)

Year 1 Year 2 Year 1 Year 2 Placebo

n=162

DAC HYP

n=156

Placebo

n=163

DAC HYP

n=163

New/enlarging T2 lesions New Gd+ T1 lesions

Reduction in

Gd+ Lesions = 86%

Gd+, gadolinium enhancing T1 lesions

Reduction in

new or

newly enlarging

T2 Lesions

= 74%

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 placebo

Year 1 of DAC HYP

66% reduction vs.

SELECT placebo

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

ps

e R

ate

Confirmed Disability Progression

over 2 Years of DAC HYP Treatment

13

50% risk reduction

(95% CI, 12-71%; P=0.015)

0.0

0.1

0.2

0.3

DAC HYP continuous

0 12 24 6 3 9 15 18 21

DAC HYP

Placebo

Placebo

16%

12%

DAC HYP

DAC HYP after placebo

6%

13%

Placebo patients start DAC HYP

Time on study (months)

Pro

po

rtio

n o

f p

ati

en

ts w

ith

co

nfi

rme

d d

isa

bilit

y p

rog

res

sio

n

DAC HYP

Sustained progression is defined as at least a 1.0 point increase on the EDSS from a SELECT baseline EDSS >= 1.0 sustained for 3 months or at least a 1.5 point increase on the EDSS from

a SELECT baseline EDSS of 0 sustained for 3 months. A cutoff of 74 days was used to determine sustained progression for 3 months.

Reduction in New/Newly Enlarging T2 Lesions

During Year 2 of DAC HYP treatment

14

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 placebo

Year 2

83% reduction vs.

SELECT placebo

Year 1

79% reduction vs.

SELECT placebo

Year 2

88% reduction vs.

SELECT placebo

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

ne

w T

2 le

sio

ns

(m

ea

n)

Impact of Washout / Re-initiation of DAC HYP

15

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

16

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

Ne

w G

d+

Les

ion

s (

me

an

)

Year 1 Year 2 Year 1 Year 2

Safety Results

17

Adverse Event Summary

18

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*

* 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

19

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

DAC HYP Starters

Year 1 of DAC HYP

DAC HYP Continuous

Year 2 of DAC HYP

DAC HYP Washout /

Reinitiation

ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal

PD Results

20

CD56bright NK Cell Counts During Washout and

Continuous DAC HYP treatment

21 NK, natural killer

0 8 16 24 32 40 48 56 64 72 80 88 96 104 0

20

40

60

80

100 2-Year Continuous Treatment

With 24-Week Washout

Time (Weeks)

Med

ian

(25 th

-75 th

perc

en

tile

s)

CD

56 b

rig

ht N

K c

ell

co

un

t (c

ells/m

m 3

)

Summary (1)

Evidence for high efficacy in subjects initiating DAC HYP

59% reduction in ARR after treatment start vs. year 1 placebo phase

(P<0.001)

54% reduction in EDSS progression after treatment start vs. year 1

placebo 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

22

Summary (2)

Pharmacodynamic changes plateau by second year of treatment

and are reversible over 24-week washout

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 HYP 150mg continuous treatment group

23

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 AbbVie Biotherapeutics. Ed Parr of UBC Scientific

Solutions provided editorial support to the authors in the development of this presentation, which

was funded by Biogen Idec and AbbVie Biotherapeutics.