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6/18/2015 2015 Annual Meeting of the Consortium of Multiple Sclerosis Centers May 27 30, 2015 Indianapolis, IN The Effects of Daclizumab High Yield Process (DAC HYP) on Patient Centered Functional Outcomes: Results From the DECIDE Study

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The Effects of Daclizumab High‐Yield Process (DAC HYP) on Patient‐Centered Functional Outcomes: Results From the DECIDE Study

Michael Kaufman, MD May 29, 2015

2015 Annual Meeting of the Consortium of Multiple Sclerosis Centers May 27‐30, 2015 Indianapolis, IN

Michael Kaufman, MD,1 Ludwig Kappos, MD,2 Krzysztof Selmaj, MD,3 Douglas Arnold, MD,4,5 Eva Havrdova, MD,6 Alexey Boyko, MD,7 Heinz Wiendl, MD,8 John Rose, MD,9 Steven Greenberg, MD,10 Wei Ma, PhD,11 Ping Wang, PhD,11 Lou Barbato, MD11

1Cole Neurological Institute, University of Tennessee, Knoxville, Knoxville, TN, USA; 2University Hospital Basel, Basel,

Switzerland; 3Medical University of Lodz, Lodz, Poland; 4McGill University, Montreal, Canada; 5NeuroRx Research, Montreal, Canada; 6First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic; 7Russian National Research Medical University named after N.I. Pirogov and the Moscow Multiple Sclerosis Center, Moscow, Russia; 8University of Münster, Münster, Germany; 9Department of Neurology, University of Utah and Neurovirology Research Laboratory VASLCHCS, Imaging and Neuroscience Center, Salt Lake City, UT, USA; 10AbbVie Biotherapeutics Inc., Redwood City, CA, USA; 11Biogen, Cambridge, MA, USA 2

Disclosures

This study was supported by Biogen and AbbVie Biotherapeutics Inc.
Michael Kaufman: honoraria and research support from Biogen; financial support from Bayer HealthCare, EMD Serono, Novartis, and Teva;

consultant for the Department of Defense and Dechert

Ludwig Kappos: received in the last 3 years and used exclusively for research support: steering committee/advisory board/consulting fees from

Actelion, Addex, Bayer HealthCare, Biogen, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi‐Aventis, Santhera, Siemens, Teva, UCB, and Xenoport; speaker fees from Bayer HealthCare, Biogen, Merck, Novartis, Sanofi‐Aventis, and Teva; support of educational activities from Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi, and Teva; royalties from Neurostatus Systems GmbH; grants from Bayer HealthCare, Biogen, the European Union, Merck, Novartis, Roche, Roche Research Foundations, the Swiss Multiple Sclerosis Society, and the Swiss National Research Foundation

Krzysztof Selmaj: compensation for consulting services from Genzyme, Novartis, Ono, Roche, Synthon, and Teva; speakers fees from Biogen
Douglas Arnold: honoraria from Bayer HealthCare, Biogen, EMD Serono, Genentech, Genzyme, GlaxoSmithKline, Merck Serono, Novartis, Roche,

and Teva; employee of and stockholder in NeuroRx Research

Eva Havrdova: honoraria and research support from Bayer HealthCare, Biogen, Genzyme, Merck Serono, Novartis, and Teva; advisory board for

Biogen, Genzyme, Merck Serono, Novartis, and Teva

Alexey Boyko: consulting/speaker fees from and advisory board for Bayer HealthCare, Biogen, Genzyme, Merck Serono, Novartis, Nycomed,

Sanofi‐Aventis, and Teva

Heinz Wiendl: consulting fees and honoraria from Bayer HealthCare, Biogen, Fresenius Medical Care, GlaxoSmithKline, GW Pharmaceuticals, Merck

Serono, Novartis, Sanofi‐Genzyme, and Teva; grants/contracts with Bayer HealthCare, Biogen, Deutsche Forschungsgesellschaft, the Else Kröner Fresenius Foundation, the Fresenius Foundation, the German Ministry for Education and Research, the Hertie Foundation, the Interdisciplinary Center for Clinical Studies in Münster, Germany, Merck Serono, Novartis, the NRW Ministry of Education and Research, the RE Children’s Foundation, Sanofi‐Genzyme, and Teva

John Rose: research support from AbbVie Biotherapeutics Inc., Biogen, Cummings Foundation, the National Multiple Sclerosis Society, the National

Institutes of Health, Teva, and Veterans Affairs

Steven Greenberg: full‐time employee of AbbVie Biotherapeutics Inc.
Wei Ma, Ping Wang, and Lou Barbato: full‐time employees of Biogen
Biogen and AbbVie Biotherapeutics Inc. provided funding for editorial support in the development of this presentation. Rebecca Jarvis, PhD, (Excel

Scientific Solutions, Southport, CT, USA) provided editorial support. Biogen and AbbVie Biotherapeutics Inc. reviewed and provided feedback on the

presentation. The authors had full editorial control of the presentation and provided their final approval of all content

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Introduction

Ambulation and cognition are priorities for patients with

multiple sclerosis (MS)

The randomized, double‐blind DECIDE study found daclizumab

high‐yield process (DAC HYP) 150 mg subcutaneous (SC) reduced clinical and radiographic disease activity in patients with relapsing‐remitting MS (RRMS) compared with interferon (IFN) beta‐1a 30 mcg intramuscular (IM)1

– DAC HYP was associated with elevated risk of infections, cutaneous adverse events, and hepatic enzyme abnormalities1

1. Kappos L, et al. Daclizumab HYP versus interferon beta‐1a in relapsing‐remitting multiple sclerosis: Primary results of the DECIDE study. Presented at: 67th Annual Meeting
f the American Academy of Neurology; April 18‐25, 2015; Washington, DC.

Objective

To evaluate the effects of DAC HYP vs. IM IFN beta‐1a on

ambulation, hand/arm dexterity, and cognition, using the Multiple Sclerosis Functional Composite (MSFC) and Symbol Digit Modalities Test (SDMT) in DECIDE

1. Kappos L, et al. Daclizumab HYP versus interferon beta‐1a in relapsing‐remitting multiple sclerosis: Primary results of the DECIDE study. Presented at: 67th Annual Meeting
f the American Academy of Neurology; April 18‐25, 2015; Washington, DC.

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DECIDE Study Design Overview

Changes in MSFC and SDMT were included as tertiary endpoints in DECIDE

96‐ to 144‐week treatment period Patients with RRMS (N=1841) IFN beta‐1a 30 mcg IM every 1 week (n=922) IFN beta‐1a 30 mcg IM every 1 week (n=922) DAC HYP 150 mg SC every 4 weeks (n=919) DAC HYP 150 mg SC every 4 weeks (n=919) Follow‐up

EDSSa EDSS EDSS EDSS EDSS EDSS

EDSS = Expanded Disability Status Scale; MRI = magnetic resonance imaging. aAlso assessed at Weeks 60, 72, 84, 108, 120, 132, and 144. bAlso assessed at Weeks 60, 72, 84, 120, 132, and 144. cAlso assessed at Weeks 72, 120, and 144. 1. Polman CH, et al. Ann Neurol. 2005;58(6):840‐846.

Inclusion criteria:

Age 18–55 years
Confirmed RRMS1
MRI consistent with MS
Baseline EDSS score 0.0‐5.0
≥ 2 relapses within 3 years

(≥ 1 in year before study) OR ≥ 1 relapse and ≥ 1 new MRI lesion within 2 years (≥ 1 event in year before study)

Time, weeks

1:1 randomization 4 8 12 16 20 24 28 32 36 40 44 48 96 144

MSFCb SDMTc SDMT SDMT SDMT MSFC MSFC MSFC MSFC MSFC

Demographics and Baseline Characteristics

Characteristic IFN beta‐1a 30 mcg IM n=922 DAC HYP 150 mg SC n=919 Mean (SD) age, y 36.2 (9.3) 36.4 (9.4) Female, n (%) 627 (68) 625 (68) Mean (SD) duration of disease, ya 4.1 (4.7) 4.2 (5.0) Mean (SD) relapses within previous year 1.6 (0.8) 1.5 (0.7) Mean (SD) EDSS score 2.5 (1.3) 2.5 (1.2) Previous DMT, n (%)b 376 (41) 380 (41) Mean (SD) no. of Gd+ lesions 2.3 (5.9) n=909 2.0 (5.9) n=900

No. with any Gd+ lesion, n (%)

414 (45) 398 (43) Mean (SD) no. of T2 lesions 51.8 (37.4) n=908 49.2 (35.5) n=900

DMT = disease‐modifying therapy; Gd+ = gadolinium‐enhancing. aTime since MS diagnosis. bIncludes IFN beta, glatiramer acetate, natalizumab, mitoxantrone, azathioprine, fumaric acid, laquinimod, cyclophosphamide, mycophenolic acid, fingolimod, teriflunomide, methotrexate, alemtuzumab, cladribine, immunoglobulins, temsirolimus.

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Multiple Sclerosis Functional Composite (MSFC)a

Timed 25‐Foot Walk (T25FW)

Assesses ambulatory function
Time to walk 25 feet time increase of ≥ 20% meaningful

9‐Hole Peg Test (9‐HPT)

Measures arm and hand function
Time to insert and remove 9 pegs first with dominant hand and

then with nondominant hand mean time for both hands 3‐Second Paced Auditory Serial Addition Test (PASAT‐3)

Measures cognition function
Patient listens to a series of 61 spoken numbers separated by 3‐

second intervals, and each number must be added to the previous number number of correct additions

aDeveloped by the National Multiple Sclerosis Society Clinical Outcomes Assessment Task Force, 1997. Polman CH, Rudick RA. Neurology. 2010;74(suppl 3):S8‐S15.

MSFC: A Measure of Disability in MS

Summary of the 3 MSFC components (T25FW, 9‐HPT, and PASAT‐3):
Generate appropriately weighted composite using the z score

– z scores are the number of standard deviations between scores for the individual and the reference population (e.g., MS population) – Negative change in MSFC z scores compared with Baseline or prior measurements indicate neurologic deterioration and disability progression, while a positive change in z score indicates neurologic improvement

Polman CH, Rudick RA. Neurology. 2010;74(suppl 3):S8‐S15.

MSFC Component Unit of Measure Indicates Deterioration T25FW Time (s) Higher Score 9‐HPT Time (s) Higher Score PASAT‐3 Number Correct Lower Score

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Symbol Digit Modalities Test (SDMT)

Outcome Measures

Measure of cognition (not part of the MSFC)
Quickly screens for cerebral dysfunction in

children 8 years and older and adults Scoring

Takes < 5 minutes
Patient substitutes a number, either orally
r written, for randomized presentations of

geometric figures that are defined in a key

Smith A. Symbol Digit Modalities Test Manual. Torrance, CA: Western Psychological Services; 1973.

MSFC and SDMT Scores at Baseline

IFN beta‐1a 30 mcg IM n=922 DAC HYP 150 mg SC n=919 Median MSFC z score (25th, 75th percentiles) 0.118 (–0.377, 0.482) n=920 0.139 (–0.335, 0.491) n=916 Median T25FW z score (25th, 75th percentiles) 0.223 (–0.042, 0.372) 0.223 (–0.034, 0.372) Median 9‐HPT z score (25th, 75th percentiles) 0.035 (–0.622, 0.633) 0.065 (–0.597, 0.661) Median PASAT‐3 z score (25th, 75th percentiles) 0.264 (–0.619, 0.794) 0.352 (–0.531, 0.794) Mean (SD) SDMT score 47.66 (16.08) n=880 48.53 (15.92) n=884

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Median Change From Baseline in MSFC z Score at Weeks 24, 48, and 96

0.028 0.058 0.055 0.044 0.071 0.091 0.00 0.01 0.02 0.03 0.04 0.05 0.06 0.07 0.08 0.09 0.10 Week 24 Week 48 Week 96

Median change from Baseline in MSFC z score (25th, 75th percentiles)

IFN beta‐1a 30 mcg IM DAC HYP 150 mg SC (–0.113, 0.227) (–0.086, 0.249) (–0.136, 0.240) (–0.096, 0.287)

P=.0461a

vs. IM IFN beta‐1a

P=.0007a

vs. IM IFN beta‐1a

(–0.124, 0.170) (–0.099, 0.193)

P=.0209a

vs. IM IFN beta‐1a

Improvement

aP value for comparison between the DAC HYP and IFN beta‐1a groups was based on an analysis of covariance model based on ranks and adjusted for the baseline z score,

baseline age (≤ 35, > 35 years), and prior IFN beta use. Missing values were imputed.

Change From Baseline to Week 96 in MSFC Component z Scores

Component IFN beta‐1a 30 mcg IM n=922 DAC HYP 150 mg SC n=919 P value vs. IFN beta‐1aa Median T25FW z score (25th, 75th percentiles) –0.017 (–0.124, 0.075) 0.000 (–0.099, 0.083) .0060 Median 9‐HPT z score (25th, 75th percentiles) 0.017 (–0.273, 0.291) 0.063 (–0.195, 0.356) .0016 Median PASAT‐3 z score (25th, 75th percentiles) 0.177 (–0.088, 0.442) 0.177 (–0.088, 0.530) .0411

aP value for comparison between the DAC HYP and IFN beta‐1a groups was based on an analysis of covariance model based on ranks and adjusted for the baseline z score,

baseline age (≤ 35, > 35 years), and prior IFN beta use. Missing values were imputed.

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‐0.017 0.017 0.177 0.063 0.177 ‐0.05 0.00 0.05 0.10 0.15 0.20 0.25

T25FW 9‐HPT PASAT‐3 Median change from Baseline in MSFC component z score (25th, 75th percentiles)

IFN beta‐1a 30 mcg IM DAC HYP 150 mg SC (–0.273, 0.291) (–0.195, 0.356) (–0.088, 0.442) (–0.088, 0.530)

P=.0016a

vs. IM IFN beta‐1a

P=.0411a

vs. IM IFN beta‐1a

(–0.124, 0.075) (–0.099, 0.083)

P=.0060a

vs. IM IFN beta‐1a

Change From Baseline to Week 96 in MSFC Component z Scores

aP value for comparison between the DAC HYP and IFN beta‐1a groups was based on an analysis of covariance model based on ranks and adjusted for the baseline z score,

baseline age (≤ 35, > 35 years), and prior IFN beta use. Missing values were imputed.

Median Change from Baseline in T25FW time

0.00 0.05 0.10 0.15 0.20 0.25 12 24 36 48 60 72 84 96

Median change from Baseline in T25FW, s Study week

IFN beta‐1a 30 mcg IM DAC HYP 150 mg SC

Worsening

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Median Change From Baseline in 9‐HPT

‐0.4 ‐0.3 ‐0.2 ‐0.1 0.0 0.1 0.2 0.3 0.4 12 24 36 48 60 72 84 96

Median change from Baseline in 9‐HPT time, s Study week

IFN beta‐1a 30 mcg IM DAC HYP 150 mg SC

Improvement Worsening

Median Change From Baseline in Number of PASAT‐3 Items

0.0 0.5 1.0 1.5 2.0 2.5 12 24 36 48 60 72 84 96

Median change from Baseline in no. of PASAT‐3 items Study week

IFN beta‐1a 30 mcg IM DAC HYP 150 mg SC

Improvement

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Mean (SE) Change From Baseline in SDMT Score

Mean Changes from Baseline in SDMT

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 24 48 72 96

Mean (SE) change from Baseline in SDMT score Study week

IFN beta‐1a 30 mcg IM DAC HYP 150 mg SC

P=.6056 P=.1491 P=.0274 P=.6379

IFN beta‐1a 30 mcg IM n=839 n=761 n=713 n=682 DAC HYP 150 mg SC n=851 n=800 n=749 n=720 P value is for DAC HYP vs. IM IFN beta‐1a and was based on a random effects model with all post‐Baseline data. Included in the model were treatment as the fixed effect, time and intercept as the random effects, and interaction terms of treatment and time, adjusting for baseline SDMT score, baseline age (≤ 35, > 35 years), and prior IFN beta use.

Conclusions

Over 2–3 years of treatment, DAC HYP showed greater improvement

compared with IM IFN beta‐1a on patient‐centered measures of functional disability

– Improvement on MSFC composite z score (P=.0007) and all z scores of all subcomponents (P<.05) – Improvement on SDMT (P=.0274)

The findings of these objective measures of function and cognition

support the findings that DAC HYP demonstrated superior efficacy to IM IFN beta‐1a across key clinical and radiographic MS outcome measures1

DAC HYP has the potential to be a new treatment option for patients

with RRMS

1. Kappos L, et al. Daclizumab HYP versus interferon beta‐1a in relapsing‐remitting multiple sclerosis: Primary results of the DECIDE study. Presented at: 67th Annual Meeting
f the American Academy of Neurology; April 18‐25, 2015; Washington, DC.

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BACK UP

Median Change From Baseline to Weeks 24, 48, and 96 in T25FWa

Study visit IFN beta‐1a 30 mcg IM n=922 DAC HYP 150 mg n=919 Median change at Week 24 (25th, 75th percentiles), s 0.000 (–0.350, 0.500) 0.000 (–0.400, 0.400) Median change at Week 48 (25th, 75th percentiles), s 0.000 (–0.450, 0.500) 0.000 (–0.500, 0.450) Median change at Week 96 (25th, 75th percentiles), s 0.100 (–0.450, 0.750) 0.000 (–0.500, 0.600)

aIncrease in time indicates worsening.

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T25FW z Score: Change From Baseline to Weeks 24, 48, and 96

Study visit IFN beta‐1a 30 mcg IM n=922 DAC HYP 150 mg SC n=919 P value vs. IFN beta‐1aa Median change at Week 24 (25th, 75th percentiles) 0.000 (–0.083, 0.058) 0.000 (–0.066, 0.066) .1299 Median change at Week 48 (25th, 75th percentiles) 0.000 (–0.083, 0.075) 0.000 (–0.075, 0.083) .0894 Median change at Week 96 (25th, 75th percentiles) –0.017 (–0.124, 0.075) 0.000 (–0.099, 0.083) .0060

z scores were calculated based on a reference population mean of 6.896 and SD of 6.034 for the T25FW; a mean of 0.047 and SD of 0.011 for the 9‐HPT; and a mean of 47.011 and SD of 11.321 for the PASAT‐3. Observed data after patients switched to alternative MS medications are excluded. Missing data up to Week 96 are imputed as described in the statistical analysis plan. aP value for comparison between the DAC HYP and IFN beta‐1a groups was based on an analysis of covariance model based on ranks and adjusted for baseline z score, baseline age (≤ 35, > 35 years), and prior IFN beta use.

9‐HPT z Score: Change From Baseline to Weeks 24, 48, and 96

Study visit IFN beta‐1a 30 mcg IM n=922 DAC HYP 150 mg SC n=919 P value vs. IFN beta‐1aa Median change at Week 24 (25th, 75th percentiles) 0.001 (–0.213, 0.228) 0.025 (–0.178, 0.260) .1010 Median change at Week 48 (25th, 75th percentiles) 0.031 (–0.218, 0.285) 0.063 (–0.180, 0.317) .0756 Median change at Week 96 (25th, 75th percentiles) 0.017 (–0.273, 0.291) 0.063 (–0.195, 0.356) .0016

aP value based on an analysis of covariance model based on ranks and adjusted for baseline z score, baseline age (≤ 35, > 35 years), and prior IFN beta use. Missing values

were imputed.

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PASAT‐3 z Score: Change From Baseline to Weeks 24, 48, and 96

Study visit IFN beta‐1a 30 mcg IM n=922 DAC HYP 150 mg SC n=919 P value vs. IFN beta‐1aa Median change at Week 24 (25th, 75th percentiles) 0.088 (–0.177, 0.353) 0.088 (–0.177, 0.353) .3238 Median change at Week 48 (25th, 75th percentiles) 0.088 (–0.088, 0.442) 0.088 (–0.177, 0.442) .3177 Median change at Week 96 (25th, 75th percentiles) 0.177 (–0.088, 0.442) 0.177 (–0.088, 0.530) .0411

aP value based on an analysis of covariance model based on ranks and adjusted for baseline z score, baseline age (≤ 35, > 35 years), and prior IFN beta use. Missing values

were imputed.

Median T25FW Score

5.0 5.2 5.4 5.6 5.8 6.0 12 24 36 48 60 72 84 96

Median T25FW time, s Study week

IM IFN beta‐1a DAC HYP 150 mg

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Median 9‐HPT Time

19.0 19.5 20.0 20.5 21.0 21.5 22.0 22.5 23.0 12 24 36 48 60 72 84 96

Median 9‐HPT time, s Study week

IM IFN beta‐1a DAC HYP 150 mg 26

Median Number of PASAT‐3 Items

40 45 50 55 60 12 24 36 48 60 72 84 96

Median no. of PASAT‐3 items Study week

IM IFN beta‐1a DAC HYP 150 mg