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Overview on the Current Antibody Treatments for Multiple Sclerosis Gavin Giovannoni

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Overview on the Current Antibody Treatments for Multiple Sclerosis

Gavin Giovannoni

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Disclosures

Over the last 15 years I have received personal compensation for participating in advisory boards in relation to clinical trial design, trial steering committees, and data and safety monitoring committees from: Abbvie, Bayer-Schering Healthcare, Biogen, Canbex, Eisai, Elan, Fiveprime, Genzyme, Genentech, GSK, GW Pharma, Ironwood, MSD, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals

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Background

1. Commonest non-disabling disease to affect young adults

2. Reduces life expectancy by ~8-10 years

3. Major socio-economic impact

4. Incidence of 6-9/100,000. Prevalence 125-250/100,000, latitudinal gradient

5. Average age of onset 31 years (majority of cases between 18-50)

6. Females:Males = 2-3:1 (increasing sex ratio)

7. Complex disease: genes, environment (sunlight/vD, EBV and smoking)

8. Presumed autoimmune

- No autoantigens identified

9. Pathologically: inflammatory demyelination with variable degrees of neuroaxonal loss and gliosis

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Approved disease-modifying therapies for MS

1994 1996 20001998 2002 2004 2006 2008 2010 2012 2014

SC IFN beta-1b1995 (RMS)

IM IFN beta-1a1997 (RMS)

SC IFN beta-1a 1998 (RMS)

Natalizumab2006 (RRMS)

Glatiramer acetate20 mg/mL

2003 (RMS)Fingolimod

2011 (RRMS)

Alemtuzumab2013 (RRMS)Teriflunomide 2013 (RRMS)

2016

Dimethyl fumarate2014 (RRMS)Peginterferon beta-1a2014 (RRMS)

Daclizumab2016 (RMS)

Glatiramer acetate40 mg/mL2015 (RMS)

Ocrelizumab2017 (RMS/PPMS)

Oral Cladribine2017 (RMS/PPMS)

2018

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Emerging therapies for MS

1994 1996 20001998 2002 2004 2006 2008 2010 2012 2014

SC IFN beta-1b1995 (RMS)

IM IFN beta-1a1997 (RMS)

SC IFN beta-1a 1998 (RMS)

Natalizumab2006 (RRMS)

Glatiramer acetate20 mg/mL

2003 (RMS)Fingolimod

2011 (RRMS)

Alemtuzumab2013 (RRMS)Teriflunomide 2013 (RRMS)

2016

Dimethyl fumarate2014 (RRMS)Peginterferon beta-1a2014 (RRMS)

Daclizumab2016 (RMS)

Glatiramer acetate40 mg/mL2015 (RMS)

Ocrelizumab2017 (RMS/PPMS)

Oral Cladribine2017 (RMS/PPMS)

2018

Rituximab Ofatumumab

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Agent Target Proposed MOA Phase

Natalizumab α4 subunit of α41 and α47 integrins Inhibition of lymphocyte binding to endothelial receptors, preventing entry into the CNS (59)

Approved

Alemtuzumab CD52 on lymphocyte and monocyte cell surfaces

Depletion of CD52+ cells Approved

Daclizumab CD25 on activated T-lymphocytes Antagonizes CD25-mediated signalling blocking T-cell activation and expansion; expands regulatory CD56bright NK cells

Phase 3

Ocrelizumab CD20 Depletes CD20+ B cells Phase 3

Ofatumumab CD20 Inhibits early-stage B lymphocyte activation Phase 2

Ustekinumab P40 subunit of IL-12 and IL-23 Disrupts IL-12– and IL-23–mediated signalling which would otherwise elicit inflammatory and immune responses

Phase 2

Tabalumab (LY2127399) BAFF Counteracts dysregulated BAFF expression which may contribute to MS via effects on abnormal B lymphocyte activation, proliferation, survival, and Ig secretion

Phase 2

Secukinumab IL-17A Inhibition of the release of pro-inflammatory cytokines and chemokines.

Phase 2

GNbAC1 Envelope protein of MS-associated retrovirus

Blocks upstream pathophysiology of MS Phase 2

Vatelizumab VLA-2 Interferes with collagen-binding in areas of inflammation Phase 2

Opicinumab Anti-Lingo-1 Binding of the Fab (fragment antibody-binding) region of the antibody to LINGO-1, and the resulting complex formation, blocks epitopes in the LINGO-1 IgG domain that function in oligodendrocyte differentiation

Phase 2

mAb

s in

MS

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Two compartment model

T Te

B

APC T

TcTc

TcTc

B

Treg

BBB CNS

Bi

Te

Te

Bi

Te

Te

B

TregTre

g

Systemic immune

compartment

APC, antigen presenting cells; B, B lymphocytes; BBB, blood-brain barrier; Bi, inflammatory B cells; CNS, central nervous system; Tc, T lymphocytes; Te, encephalitogenic T cells; Treg, regulatory T cells. Figure is reproduced with permission from Wiendl H, Kieseier B. Nat Rev Neurol. 2013;9:125-61. Wiendl H, Kieseier B. Nat Rev Neurol. 2013;9:125-6

Intrathecal immune compartment

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Natalizumab

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Selewski . AJNR.2010

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Natalizumab Efficacy

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Kleinschmidt-DeMasters,et al. N Engl J Med. 2005 Jul 28;353(4):369-74.

PML complicating treatment with natalizumab and IFNb-1a for MS

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Global Natalizumab PML Incidence Estimates by Treatment Epoch: March 2016

Biogen Data on File, July 2016

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Natalizumab PML risk stratification tool

www.ms-res.org

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Determinants of survival in PML

Marzocchetti et al., Neurology 2009;73:1551–1558

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Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function

Khatri et al. Neurology 2009;72:402–409

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Wenning et al. N Engl J Med. 2009;361:1075-80.

Immune reconstitution inflammatory syndrome (IRIS)

Rx: IV methylprednisolone 1g daily x 5 days, followed by tapered dose of oral steroids.

Prophylaxis: I recommend prophylactic corticosteroids if high burden of disease and/or posterior fossa involvement.

Clifford DB, et al. Lancet Neurol. 2010;9:438–446.

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Alemtuzumab

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Alemtuzumab: a humanized monoclonal antibody approved for treatment of patients with active RRMS

• A humanized monoclonal antibody that selectively targets CD52, a protein abundant on the surface of B and T lymphocytes1

• Novel dosing regimen: administered 12 mg/day via intravenous (IV) infusions on 5 consecutive days at baseline and on 3 consecutive days 12 months later2,3

• Approved for adult patients with relapsing-remitting MS (RRMS) with active disease defined by clinical or imaging features4

• First approved - EU in 20135*

1. Hu Y et al. Immunology 2009;128:260-70; 2. Cohen JA et al. Lancet 2012;380:1819-28; 3. Coles AJ et al. Lancet 2012;380:1829-39; 4. Lemtrada (alemtuzumab) Peru Summary of Product Characteristics, 2014; 5. Lemtrada (alemtuzumab) EU Summary of Product Characteristics, September 2013.

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1. Weber MS et al. Results Probl Cell Differ 2010;51:115-26; 2. Hu Y et al. Immunology 2009;128;260-70; 3.Turner MJ et al. J Neuroimmunol 2013;261:29-36; 4. Cox AL et al. Eur J Immunol 2005;35:3332-42; 5. Fox EJ. Exp Rev Neurother 2010;10:1789-97.

Alemtuzumab: mechanism of action

1. Selection

• Animal studies indicate that innate immune cells that express lower levels of CD52 are minimally or transiently impacted by alemtuzumab treatment2

2. Depletion

Decreases MS inflammation• Alemtuzumab selectively depletes

circulating T and B cells2,3

• Many lymphocytes remain present in lymphoid organs after treatment2,3

3. Repopulation

Reduces MS disease activity• Lymphocyte progenitor cells are presumably

unaffected by alemtuzumab2,4,5

• A distinctive pattern of T- and B-cell repopulation begins within weeks, potentially changing the balance of the immune system2,4,5

BT

CD52 B

CD52T T cellprecursor

Pre/Pro B cell

BCD52

T CD52

Monocytes

Macrophages

Neutrophils

Lymphocyte precursor

Targets T and B cells thought to mediate MS inflammation1

Lymphocyteprecursor

Lymphocyteprecursor

Stem cell

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T- and B-cell Pharmacodynamics• Alemtuzumab depleted circulating lymphocytes in SPMS patients treated between

1994–1997 (N=29)– CD4 and CD8 counts were 30-40% of pretreatment values 18 months later1

– B cells repopulated more rapidly, with counts reaching 179% of pretreatment values at 18 months

0.00.20.40.60.81.01.21.41.6

Pre Post(Day 2)

3 6 9 12 15 18Months after Alemtuzumab (20 mg × 5)

T ce

lls (

×10

9 /L)

0.0

0.1

0.2

0.3

0.4

0.5

B ce

lls (

×10

9 /L)

B cells

CD4+ T cellsCD8+ T cells

Coles AJ et al. Lancet 1999;354:1691-5.

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CARE-MS I: Alemtuzumab Pharmacokinetics

Unique PK/PD profile of alemtuzumab allows for 2 short treatment courses

– Alemtuzumab is administered on 5 consecutive days at Month 0 and on another 3 days 12 months later

– Serum concentrations are low or undetectable within 1 month after dosingLycke J et al. EFNS 2012.

Alemtuzumab administration

1500

40004500

2500

3500

5000

2000

3000

1000

Day 0

Con

cent

ratio

n (n

g/m

L)

Day 5 Day 10 Day 15 Day 20 Day 25 Month 1

First treatment course

Time

1500

4000

4500

2500

3500

5000

2000

3000

1000

0 1 3 6 9 12 2415 18 21

Con

cent

ratio

n (n

g/m

L)

13

Months

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CARE-MS II3,4

CARE-MS Extension: NEDA Through Year 5Patients Treated With Alemtuzumab 12 mg in Core Studies

The proportion of alemtuzumab-treated patients with no evidence of disease activity remained stable through Year 5

No evidence of disease activity: absence of clinical disease activity (relapse and 6-month sustained accumulation of disability) and MRI activity (new Gd-enhancing lesions, and new/enlarging T2 hyperintense lesions).

1. Compston DA et al. AAN 2015; Platform S4.007; 2. Arnold D et al. ECTRIMS 2015; 3. Havrdova E et al. AAN 2015; Poster P7.276; 4. Traboulsee A et al. ECTRIMS 2015.

P=0.0001(↑61.2%)

P<0.0001(↑82.6%)

Prop

ortio

n of

Pati

ents

, % (9

5% C

I)

SC IFNB-1a 44 μgAlemtuzumab 12 mg

SC IFNB-1a 44 μgAlemtuzumab 12 mg

Prop

ortio

n of

Pati

ents

, % (9

5% C

I)

CARE-MS I1,2

P=0.0053 (↑32.2%)

P<0.0001(↑44.5%)

174 369 169 354No. of patients

326 324 187 414 171 402 361 336319 325No. of patients

301 311

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Daclizumab

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MS treatments mostly rely on direct targeting of proinflammatory cells

B, B cell; BBB, blood–brain barrier; CNS, central nervous system; HCAR2, hydroxycarboxylic acid receptor 2; MoA, mechanism of action; nrf 2, nuclear factor (erythroid-derived 2)-like 2; S1P1, sphingosine-1-phosphate receptor 1; T, T cell; Th, T-helper cell.

Adapted from: Loleit V, et al. Curr Pharm Biotechnol. 2014;15:276–96; Scannevin R, et al. J Pharmacol Exp Ther. 2012;341:274–84; Chen H, et al. J Clin Invest. 2014;124:2188–92.

AlemtuzumabCD52

Lysis of mature B and T cells

Proposed MoA: Anti-migratory

FingolimodNatalizumab

Lymph node

BBB

CNS

S1P1

B

Tα4-integrin

Proposed MoA: Pleiotropic effects

Limits pyrimidine availability for

rapid cell division

Teriflunomide

IFNs

Activation of 100+ IFN-response genes

Activation of 700+ nrf 2 responsive genes and HC-AR2

Glatiramer acetate

Modulation of Th1:Th2 balance

Dimethyl fumarate

Proposed MoA: Targeted cell lysis

Periphery

Proposed MoA: Reduced proliferation

CD20

Ocrelizumab CladribineIL2 modulatorexpands CD56-bright NK cellsDaclizumab (anti-CD25)

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Daclizumab blocks IL-2 binding to high-affinity IL-2 receptors on activated T cells

Amaravadi L, et al. Poster presentation at AAN 2015;P1.149; Bielekova B. Neurotherapeutics. 2013;10:55–67; Pfender N, Martin R. Exp Neurol. 2014;262:44–51.

• IL-2 signalling induces expansion and differentiation of activated T cells• Daclizumab binds the α chain (CD25)

and blocks IL-2 association with the high-affinity IL-2 receptor

• IL-2 signalling induces expansion and activation of CD56bright NK cells• Daclizumab does not prevent

IL-2 signalling through the intermediate-affinity IL-2 receptor

Intermediate-affinity IL-2 receptorHigh-affinity IL-2 receptor

CD4+Tact cell CD56bright

β γ β γIL-2 IL

-2α

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Mode of action of daclizumab

Adapted from: Amaravadi L, et al. Poster presentation at AAN 2015;P1.149; Zinbryta® (daclizumab) SmPC. July 2016.

IL-2

Daclizumab blocks high-affinity IL-2 receptor signalling, resulting in higher levels of IL-2 available for signalling through intermediate-affinity IL-2 receptor

IL-2 intermediate-affinity (βγ) receptor

IL-2 high-affinity (βαγ) receptor

Daclizumab

Activation

CD4+

CD4+Tact cell

CD4+Tact cell

CD56bright

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Effects of IL-2 pathway modulation include selective antagonism of activated T-cell responses and expansion of immunoregulatory CD56bright NK cells

Adapted and elaborated from: Amaravadi L, et al. Poster presentation at AAN 2015;P1.149; Zinbryta® (daclizumab) SmPC. July 2016.

Activation

CD4+

CD4+Tact cell

CD4+Tact cell

CD56bright CD56brightCD56bright

CD56brightCD56bright

CD56bright

IL-2

IL-2 intermediate-affinity (βγ) receptor

IL-2 high-affinity (βαγ) receptor

Daclizumab

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Daclizumab induces a sustained increase in serum IL-2 concentrations

*Difference first observed; P<0.0001. IQR, interquartile range.Amaravadi L, et al. Poster presentation at AAN 2015;P1.149; Zinbryta® (daclizumab) SmPC. July 2016.

0 4 8 16 24 40 48 52

Time (weeks)

0

2

4

6

8

10

Med

ian

(± IQ

R) I

L-2

(pg/

mL) Daclizumab 150mg (n=129)

Placebo (n=38)

*

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CD25 blockade prevented IL-2 bindingbut resulted in a moderate reduction in T-cell numbers

NK, natural killer.Statistically significant differences (P<0.05) between baseline, combination therapy, and monotherapy time points are indicated by horizontal bidirectional arrows (↔) in the graphs.

Bielekova B, et al. Arch Neurol. 2009;66:483–89.

CD8+ T cellsCD4+ T cells

0

600

800

200

400

Mo

-3

Mo

-1

Mo

2.5

Mo

4.5

Mo

6.5–

8.6

Mo

10.5

Mo

12.5

–14.

5

Abs

olut

e nu

mbe

r of c

ells

per

ul o

f blo

od

IFN-β IFN-β+dacliz

daclizumab

0

2000

2500

500

Mo

-3

Mo

-1

Mo

2.5

Mo

4.5

Mo

6.5–

8.6

Mo

10.5

Mo

12.5

–14.

5

Abs

olut

e nu

mbe

r of c

ells

per

ul o

f bl

ood

IFN-β IFN-β+dacliz

daclizumab

1500

1000

CD56bright NK cells

0

200

250

50

Mo

-3

Mo

-1

Mo

2.5

Mo

4.5

Mo

6.5–

8.6

Mo

10.5

Mo

12.5

–14.

5

Abs

olut

e nu

mbe

r of c

ells

per

ul o

f bl

ood

IFN-β IFN-β+dacliz

daclizumab

1500

100

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During daclizumab treatment, mean cell counts for the major immune subsets remained within normal ranges

LLN, lower limit of normal.*P<0.05 vs placebo; **P<0.01 vs placebo.

Elaborated from: Gold R, et al. Lancet. 2013;381:2167–75; Zinbryta® (daclizumab) SmPC. July 2016.

Total lymphocytes CD4+ cells CD8+ cells1000

750

500

250

0Baseline Week 24 Week 52

Mea

n (±

SD) C

D4+

(cel

ls/m

m3 ) 800

600

400

200

0Baseline Week 24 Week 52

Mea

n (±

SD) C

D8+

(cel

ls/m

m3 )

+3.9%

-4.4%

**

+2.8%

-7.0%

**

+4.8%

-1.3%*

+1.9%

-3.6%*

+4.1%

-4.7%

**

+3.1%

-9.1%

**

Daclizumab 150 mg (n=184) Placebo (n=179)

Total lymphocyte, T- and B-cell counts decreased on average by ≤10% from baseline during the first year of treatment

2000

1500

1000

500

0Baseline Week 24 Week 52

Mea

n (±

SD)

tota

l lym

phoc

ytes

(cel

ls/m

m3 )

LLN

Page 31: Pegs m abs in rx ms

Primary endpoint: Annualised relapse rate

CI, confidence interval.1. Gold R, et al. Lancet. 2013;381:2167–75; 2. Zinbryta® (daclizumab) SmPC. July 2016; 3. Kappos L, et al. N Engl J Med. 2015;373:1418–28.

Placebo (n=196)

Daclizumab150 mg (n=201)

Daclizumab 300 mg (n=203)

54%relative

reductionP<0.0001

50%relative

reductionP=0.00015

At Week 521,2 Up to Week 1442,3

IM IFN beta-1a(n=922)

Daclizumab150 mg(n=919)

45%relative

reductionP<0.0001

SELECT: vs placebo DECIDE: vs IFN beta-1a

The 300 mg dose did not provide additional benefit over the licensed 150 mg dose

Ann

ualis

ed re

laps

e ra

te (9

5%

CI)

Ann

ualis

ed re

laps

e ra

te (9

5%

CI)

Page 32: Pegs m abs in rx ms

24-week confirmed disability progression

*Post-hoc analysis. †Tertiary endpoint. ‡Secondary endpoint. HR, hazard ratio.1. Zinbryta® (daclizumab) SmPC. July 2016; 2. Biogen, data on file; 3. Kappos L, et al. N Engl J Med. 2015;373:1418–28.

No. at risk

SELECT: vs placebo1,2 DECIDE: vs IFN beta-1a1,3

196201

192198

183190

171185

167184

114132

0 12 24 36 48 60 72 84 96 108 120 132 144

27% relative risk reductionHR=0.73 (95% CI: 0.55–0.98)

P=0.03

922919

878897

829863

790817

743796

704755

669722

647688

624662

462502

362361

254266

134131

Daclizumab (n=201) Placebo (n=196)

Time on study (weeks) No. at risk

13%

18%

0 12 24 36 48 52

20

10

0

25

15

5

76% relative risk reductionHR=0.24 (95% CI: 0.09–0.63)

P=0.0037

2.6%

11%

Up to Week 52* Up to Week 144†

No. at riskTime on study (weeks) No. at risk

Patie

nts

with

con

firm

ed

disa

bilit

y pr

ogre

ssio

n (%

)

20

15

10

5

0

25

• 12-week confirmed disability progression: 57% relative risk reduction vs placebo† (HR=0.43, 95% CI: 0.21-0.88; P=0.021); 16% relative risk reduction vs IFN beta-1a‡ (HR=0.84, 95% CI: 0.66-1.07; P=0.16)1

Page 33: Pegs m abs in rx ms

NEDA, no evidence of disease activity; OR, odds ratio.*Post-hoc analyses. NEDA was defined as: no clinical relapses, no onset of 12-week confirmed disability progression, no new/newly enlarging T2 hyperintense lesions vs the start of the period and no Gd+ lesions

(at Week 24 for baseline–Week 24 and at Week 96 for Weeks 24–96). NEDA status was considered missing for patients with missing assessments but whose available outcomes satisfied NEDA criteria.Giovannoni G, et al. Poster presentation at ECTRIMS 2016;P664.

Patients achieving no evidence of disease activity

DECIDE: vs IFN beta-1a

Patie

nts

achi

evin

g N

EDA

(%)

OR: 2.96P<0.0001

IM IFN beta-1a

Daclizumab

n=347/776

n=173/773

n=367/884

n=282/864

EDSSBrain

MRI

✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓0 12 24 36 48 60 72 84 96-144

OR: 1.51P<0.0001

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Hepatic injury

*Only patients treated with daclizumab 150 mg in development programme studies are shown; patients exposed to daclizumab 300 mg dose in SELECT and/or SELECTION not represented. Duration was defined as length of time in days from the last ALT or AST measurement ≤1× ULN until return of both ALT and AST to ≤1.5× ULN.

ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal.1. Giovannoni G, et al. Mult Scler Rel Dis. 2016;9:36–46; 2. Kappos L, et al. N Engl J Med. 2015;373:1418–28. 3. Zinbryta® (daclizumab) SmPC. July 2016; 4. Fam S, et al. Poster presentation at EAN 2016;P31134.

• Elevation of transaminases in daclizumab-treated patients occurred throughout treatment 1,4

• Most elevations were asymptomatic and resolved spontaneously3,4

• In DECIDE median (25th–75th percentiles) duration of ALT or AST elevation >5× ULNwas 87.0 (50.0–128.0) days in daclizumab group vs 100.0 (75.5–136.5) in IM IFN beta-1a 4

INTEGRATED SAFETY ANALYSIS1*

DECIDE(2–3 y; vs IFN beta-1a)1–3

Daclizumab 150 mg(n=1943)

IM IFN beta-1a(n=922)

Daclizumab 150 mg (n=919)

Hepatic events, % 15 14 16Serious hepatic events, % <1 <1 1ALT or AST, %

≥3× ULN 9 9 10>5× ULN 6 3 6

Discontinuation due to hepatic events, % 5 4 5

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Skin reactions

*Only patients treated with daclizumab 150 mg in development programme studies are shown; patients exposed to daclizumab 300 mg dose in SELECT and/or SELECTION not represented.1. Giovannoni G, et al. Mult Scler Rel Dis. 2016;9:36–46; 2. Zinbryta® (daclizumab) SmPC. July 2016; 3. Kappos L, et al. N Engl J Med. 2015;373:1418–28; 4. Krueger JG, et al. Adv Ther. 2016;33:1231–45.

INTEGRATED SAFETY ANALYSIS1,2*

DECIDE(2-3 y, vs IFN beta-1a)1–3

Daclizumab 150 mgn=1943

IM IFN beta-1an=922

Daclizumab 150 mg n=919

Skin reactions, % 32 19 37Serious skin reactions, % 2 <1 2Discontinuation due to skin reactions, % 4 1 5

• In DECIDE, incidence of events assessed as related to treatment by investigators was 7% in IM IFN beta-1a and 15% in daclizumab groups4

• In daclizumab studies the most common skin reactions were rash, dermatitis and eczema1–4

• In DECIDE, the majority (94%) of events associated with daclizumab were mild or moderate in severity2,4

• In DECIDE, serious skin reactions in ≥2 patients included dermatitis (n=3) and angioedema (n=2) 4

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Infections

*Only patients treated with daclizumab 150 mg in development programme studies are shown; patients exposed to daclizumab 300 mg dose in SELECT and/or SELECTION not represented.1. Giovannoni G, et al. Mult Scler Rel Dis. 2016;9:36–46; 2. Kappos L, et al. N Engl J Med. 2015;373:1418–28. 3. Zinbryta® (daclizumab) SmPC. July 2016.

INTEGRATED SAFETY ANALYSIS1*

DECIDE(2–3 y, vs IFN beta-1a)1–3

Daclizumab 150 mgn=1943

IM IFN beta-1an=922

Daclizumab 150 mg n=919

Infections, % 58 57 65Serious infections, % 4 2 4

• The most common infections were upper respiratory tract infections and viral infections3

• In daclizumab studies there has been no evidence of an increased risk of opportunistic infections typically seen in immunocompromised patients1,2

• In DECIDE, median duration of infection was similar in daclizumab and IM IFN beta-1a groups 3

• Majority of patients with infections continued on treatment (discontinuation due to infections <1%) 3

Page 37: Pegs m abs in rx ms

Lymphopaenia

Zinbryta® (daclizumab) SmPC. July 2016.

• In controlled studies, incidence of total lymphocyte count <800/mm3 in daclizumab group was similar to that in placebo (SELECT: 5% versus 4%) and IM IFN beta (DECIDE: 8% versus 9%) groups

• When observed during daclizumab clinical studies, lymphopenia was mostly mild to moderate (≥500/mm3)

• Sustained severe lymphopenia (<500/mm3) was not observed in clinical studies with daclizumab

• As a precaution, monitoring of complete blood count is recommended every 3 months

Page 38: Pegs m abs in rx ms

Ocrelizumab

Page 39: Pegs m abs in rx ms

pro-B

pre-B

Stem cell

Plasma cell(long lived)

Mature naive B cell

ActivatedB cell

Lymph folliclewith germinal center

Plasmablast Memory B cell

Follicle-likeaggregates

Bystander activation

Plasma cell(long lived)

OCB

CNS Educated B cells CSF

Dendritic Cell

T cell

B cells and the brainPlasmablast

Bone Marrow Central Nervous SystemSecondary Lymphoid Tissues

CNS, central nervous system; CSF, cerebrospinal fluid; OCB, oligoclonal band.

Page 40: Pegs m abs in rx ms

Antigen presentation1,2

Autoantibody production4

1. Crawford A, et al. J Immunol 2006;176(6):3498–506. 2. Bar-Or A, et al. Ann Neurol 2010;67(4):452–61. 3. Lisak RP, et al. J Neuroimmunol 2012;246(1-2):85–95. 4. Weber MS, et al. Biochim Biophys Acta 2011;1812(2):239–45. 5. Serafini B, et al. Brain Pathol 2004;14(2):164–74.

6. Magliozzi R, et al. Ann Neurol 2010;68(4):477–93.

Ectopic lymphoid follicle-like aggregates5,6

Cytokine production2,3

B cells play key functional roles in MS

Page 41: Pegs m abs in rx ms

B cells express different surface markers throughout development

BAFF = B cell activating factor; BCMA = B cell maturation antigen; TACI = transmembrane activator and calcium-modulator and cytophilin ligand interactorImage adapted from Krumbholz M, et al. Nat Rev Neurol 2012;8(11):613–23.

1. Stashenko P, et al. J Immunol 1980;125:1678–85; 2. Loken MR, et al. Blood 1987;70:1316–24; 3. Tedder TF, Engel P. Immunol Today 1994;15:450–4; 4. Martin F, Chan AC. Annu Rev Immunol 2006;24:467–96.

CD20

CD19

CD52CD138

a4-INTEGRIN

BAFF-R

BCMA

TACI

B cell reconstitution preserved1-3

Long-term memory preserved1,2,4

Page 42: Pegs m abs in rx ms

OCR Selectively Targets Mature B Cells While Sparing Other Immune CellsCytotoxic T cells

T helper cellsNatural Killer cells

CD19 B cells

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Reduction in ARR compared with IFN β-1a Primary endpoint

ITT*Adjusted ARR calculated by negative binomial regression and adjusted for baseline EDSS score (<4.0 vs ≥4.0), and geographic region

(US vs ROW).ARR, annualized relapse rate; EDSS, Expanded Disability Status Scale; ROW, rest of the world.

46% ARR reduction vs

IFN β-1ap<0.0001

OPERA I OPERA II

47%ARR reduction

vs IFN β-1ap<0.0001

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Risk reduction: 40%HR (95% CI): 0.60 (0.45, 0.81); p=0.0006

Risk reduction: 40%HR (95% CI): 0.60 (0.43, 0.84); p=0.0025

Time to CDP for ≥12 weeks Time to CDP for ≥24 weeks

ITTCDP, confirmed disability progression; CI, confidence interval; HR, hazard ratio; IFN, interferon; OCR, ocrelizumab

15.2

9.812.0

7.6

Reduction in pre-specified pooled analysis of confirmed disability progression (CDP) at 12 and 24 weeks

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Substantial reduction in total new and/or enlarging T2 hyperintense lesions compared with

IFN β-1a

45

OPERA I

OPERA II

ITT*Adjusted by baseline T2 lesion count, baseline EDSS (<4.0 vs ≥4.0) and geographical region (US vs ROW).

EDSS, Expanded Disability Status Scale; IFN, interferon; MRI, magnetic resonance imaging; ROW, rest of the world.

41%p=0.0002

94%p<0.0001

98%p<0.0001 61%

p<0.0001

96%p<0.0001

97%p<0.0001

Page 46: Pegs m abs in rx ms

46

ITT (EDSS ≥ 2.0)*Compared using the Cochran–Mantel–Haenszel test stratified by geographic region (US vs ROW) and baseline EDSS score (<4.0 vs. ≥4.0).

NEDA

Percentage Change in Brain Volume from Baseline to

Week 9674%NEDA

improvement vs IFN β-1ap<0.0001

NEDA is defined as: no protocol-defined relapses, no CDP events, no new or enlarging T2 lesions, and no Gd-

enhancing T1 lesions

Week

Higher proportion of patients with No Evidence of Disease Activity

(NEDA) compared with IFN β-1a

OPERA I

Page 47: Pegs m abs in rx ms

n (%)

IFN β-1a44 μg

(n=826)

Ocrelizumab 600 mg(n=825)

Total number of patients with ≥1 AE 688 (83.3) 687 (83.3)

Total number of patients with ≥1 AE occurring at relative frequency ≥5% 539 (65.3) 544 (65.9)

Injury, Poisoning and Procedural ComplicationsInfusion-related reaction

General Disorders and Administration-site ConditionsInfluenza-like illnessInjection-site erythemaFatigueInjection-site reaction

Infections and InfestationsUpper respiratory tract infectionNasopharyngitisUrinary tract infectionSinusitisBronchitis

Nervous System DisordersHeadache

Psychiatric DisordersDepressionInsomnia

Musculoskeletal and Connective Tissue DisordersBack painArthralgia

80 (9.7)

177 (21.4)127 (15.4)

64 (7.7)45 (5.4)

87 (10.5)84 (10.2)

100 (12.1)45 (5.4)29 (3.5)

124 (15.0)

54 (6.5)38 (4.6)

37 (4.5)51 (6.2)

283 (34.3)

38 (4.6)1 (0.1)

64 (7.8) 2 (0.2)

125 (15.2)122 (14.8)96 (11.6)46 (5.6)42 (5.1)

93 (11.3)

64 (7.8)46 (5.6)

53 (6.4)46 (5.6)

Adverse events

47

Table includes only AEs occurring in ≥5% of patients in at least one treatment group.AE, adverse event; IFN, interferon.

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Serious adverse events

• During OPERA I and OPERA II three deaths occurred– IFN β-1a 44 μg arm: completed suicide, mechanical ileus– Ocrelizumab 600 mg arm: completed suicide

n (%)

IFN β-1a44 μg

(n=826)

Ocrelizumab 600 mg(n=825)

Overall patients with ≥1 SAE 72 (8.7) 57 (6.9)

Infections and infestations 24 (2.9) 11 (1.3)

Nervous system disorders 11 (1.3) 8 (1.0)

Injury, poisoning, and procedural complications 10 (1.2) 6 (0.7)

IFN, interferon; SAE, serious adverse event.

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1.4

0.51.

5

0.51.

7

0.9

5.1

1.30.1

Most common AE associated with ocrelizumab was infusion-related reactions (IRR)

Mostly mild to moderate in severity*,†

49

*Numbers in columns represent the proportion of patients experiencing a grade of IRR†Grading per Common Terminology Criteria (CTCAE): Grade 1 Mild; asymptomatic or mild symptoms; Grade 2 Moderate; minimal, local or noninvasive intervention indicated; Grade 3 Severe or medically

significant but not immediately life-threatening; Grade 4 Life-threatening consequences; urgent intervention indicated; Grade 5 Death related to adverse event.Note: All received 100 mg i.v. methylprednisolone.

IRR, infusion-related reaction.

Ocrelizumab

600 mg

IFN β-1a

44 μg

Grade 1

Grade 2

Grade 3

Grade 4

Dose 1

Dose 2

Dose 3

Dose 4

Dose 1

Dose 2

Dose 3

Dose 4

1.0

0.1

3.6

1.1 6.

0

1.810.

8

2.6

0.4

7.4

1.8

0.418.

3

7.4

1.7

0.1

The incidence of withdrawal due to IRRs was low in the ocrelizumab arm– 1.3% (11 patients) withdrew from ocrelizumab treatment due to an IRR during the

first infusion

Infusion 1

Infusion 2

Infusion 1

Infusion 2

Page 50: Pegs m abs in rx ms

ORATORIO PPMS

50

Confidential — For internal use only. Do not copy, distribute or use without prior written consent

Placebon=244

Ocrelizumab 600 mgn=488

Age, yr, mean (SD) 44.4 (8.3) 44.7 (7.9)

Female, n (%)  124 (50.8) 237 (48.6)

Time since symptom onset, yr, mean (SD) 6.1 (3.6) 6.7 (4.0)

Time since diagnosis, yr, mean (SD) 2.8 (3.3)  2.9 (3.2)

MS disease modifying treatment naive, n (%) 214 (87.7) 433 (88.7)

EDSS, mean (SD) 4.7 (1.2)  4.7 (1.2)

MRI findingsGd– lesions, n (%)Number of Gd+ T1 lesions, mean (SD)T2 lesion volume, cm3, mean (SD)

Normalised brain volume, cm3, mean (SD)

183 (75.3%)0.6 (1.6)

10.9 (13.0)11.0 (0.9)

351 (72.5%)1.2 (5.1)

12.7 (15.1)12.8 (0.7)

EDSS, Expanded Disability Status Scale; Gd, gadolnium; MRI, magnetic resonance imaging; SD, standard deviation; yr, year.

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Reduction in confirmed disability progression for ≥12 Weeks

Primary Endpoint

24% reduction in risk of CDP

HR (95% CI): 0.76 (0.59, 0.98); p=0.0321

Time to CDP for ≥12 weeks

Analysis based on ITT population; p-value based on log-rank test stratified by geographic region and agePatients with initial disability progression who discontinued treatment early with no confirmatory EDSS assessment were considered as having confirmed disability progression

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Reduction in confirmed disability progression for ≥24 weeks

25% reduction in risk of CDP

HR (95% CI): 0.75 (0.58, 0.98); p=0.0365

Time to CDP for ≥24 weeks

Analysis based on ITT population; p-value based on log-rank test stratified by geographic region and agePatients with initial disability progression who discontinued treatment early with no confirmatory EDSS assessment were considered as having confirmed disability progression

Page 53: Pegs m abs in rx ms

* Week 120 during the Double-Blind Treatment Period (ranked ANCOVA, MMRM)

10% change in 25-foot walk

vs. placebop=0.404

Reduction in rate of decline in walking speed

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Deaths and Malignancies

54

n (%)Placebon=239

Ocrelizumab 600 mgn=486

Deaths

1 (0.4)Road traffic accidentSudden cardiac death

Aspiration

4 (0.8)Pulmonary embolism

PneumoniaPancreas carcinoma

Pneumonia aspiration

Malignancies

2 (0.8)

Cervix adenocarcinoma in situ (N=1)Basal cell carcinoma (N=1)

11 (2.3)Breast cancers (N=4)

Endometrial adenocarcinoma (N=1)T-cell lymphoma (N=1)

Histiocytoma (sarcoma) (N=1)Basal cell carcinoma (N=3)

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Opicinumab

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Remyelination

Nogo, MAG, OMgP

Lingo-1-NgR-p75NTR

GAP-43

NCAM

Neuregulin

Slide courtesy of Klaus Schmierer.

Agents in trial

1. GSK239512: histamine H(3) receptor antagonist 

2. BIIB033: anti-LINGO-1 3. Clemastine: anti-histamine4. IRX4204 & Bexarotene: RXR-agonist 5. Etc.

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Premyelinating oligodendrocytes in chronic MS lesions1

Negative regulators of OPC differentiation have been identified2,3

Investigating LINGO-1 as a target for remyelinationand neuroprotection/neuroreparation

OPC=oligodendrocyte precursor cells; NCAM=neural cell adhesion molecule; PSA=polysialic acid; RNAi=ribonucleic acid interference.1. Chang A et al. N Engl J Med. 2002;346:165-173; 2. Adapted from Rudick RA et al. Expert Opin Biol Ther. 2008;8:1561-1570; 3. Mi S et al. Ann Neurol. 2009;65:304-315; 4. Mi S et al. Nat Neurosci. 2005;8:745-751; 5. Cadavid D et al. Presented at AAN; Philadelphia, USA; 2014:P2.262.

In vivo effects of anti-LINGO-1 in rat optic nerve crush model5

Reduced neurodegeneration and increased axonal outgrowth (arrows) vs control

Control RNAiLINGO-1 RNAiIn vitro effects of LINGO-1 blockade4

Mature oligodendrocyteOPCs

Differentiation

LINGO-1,PSA-NCAM, Notch

Anti-LINGO-1treatment

Proximal Distal

Control treatment

Fluorescein isothiocyanate-conjugated cholera toxin B–labeled axons after optic nerve crush

and vehicle injection

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Anti-LINGO-1 results in remyelination in animal models of CNS demyelination2

LPC=lysophosphatidylcholine/lysolecithin; mAb=monoclonal antibody.Adapted from 1. Mi S et al. Nature Neurosci. 2004;7:221-228; 2. Mi S et al. Ann Neurol. 2009;65:304-315.

1 µm

Control mAb Anti-LINGO-1

1 µm

Cuprizone

LPC

Demyelinated axons *Remyelinated axons

EAE

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New phase 2 study designs: Acute optic neuritis to assess neuroprotection and remyelination

1. Cadavid D et al. Presented at AAN; Philadelphia, USA; 2014:P2.2622. Cadavid D et al. Presented at AAN; Washington, USA; 2015:P7.202.

RENEW1,2

Anti-LINGO-1(multi-centre)

Anti-LINGO-1 (100 mg/kg IV Q4W x 6)

Placebo (IV Q4W x 6)

Participants with first episode of unilateral AON

(n=82)

Randomised within 4 weeks of symptom onset

Dosing period20 weeks

Assessments at24 and 32 weeks

3–5 days’ IV steroids

End of studyfollow-up 32 weeks

Primary outcome: VEP

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RENEW primary outcome: Anti-LINGO-1 and recovery of full-field VEP latency in AON

*Adjusted mean change in optic nerve conduction latency of the affected eye compared with the unaffected fellow eye at baseline, Week 24 (ANCOVA), Week 32 (MMRM). ANCOVA=analysis of covariance; ITT=intent-to-treat; MMRM=mixed-effect model repeated measure; PP=per-protocol.Adapted from 1. Cadavid D et al. Presented at AAN; Washington, USA; 2015:P008; 2. Cadavid D et al. Presented at AAN; Washington, USA; 2015:P7.202.

Placebo 100 mg/kg anti-LINGO-1

25

20

15

10

5

0PP ITT

22.24

14.69

20.83

17.34

Week 2434%

LatencyrecoveryP=0.05

17% LatencyrecoveryP=0.33

Adju

sted

mea

n ch

ange

inFu

ll-fie

ld V

EP la

tenc

y* (m

s)

n=36 n=33 n=41 n=41

PP=Subjects who completed the study, did not miss >1 dose of treatment and did not receive MS modifying therapy

ITT=All randomised subjects who received ≥1 dose of study treatment

PP ITT

22.35

13.22

21.15

15.08

Week 3241%

LatencyrecoveryP=0.01

29% LatencyrecoveryP=0.07

n=36 n=33 n=41 n=41

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SD-OCT values at baselinea

Affected eye n=77 Fellow eye n=80 Difference n=77b

RGCL/IPL thickness, μm 64.8 (7.3) 69.5 (5.6) -4.76 (5.5)aValues are mean (SD); bSD-OCT was not available in the affected eye for 3 participants (missing data were not imputed).

Mean GCL/IPL thickness at each visit in the affected eye in the ITT population up to Week 32

No difference observed in RENEW secondary OCT efficacy endpoints at W32

RGCL=retinal ganglion cell layer; SD=standard deviation.1. Cadavid D et al. Presented at ACTRIMS-ECTRIMS; Boston, USA; 2014:P731; 2. Cadavid D et al. Presented at AAN; Washington, USA; 2015:P7.202.

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Revolutionised the treatment of MSTargeted therapiesBetter outcomesComplex biologyNew insights

Anti-trafficking - rebound/IRISChallenging dogmas

T-cell vs. B-cellsCD56-bright NK cellsSecondary autoimmunity

Better outcomes, but more riskIncreased monitoring requirement, e.g. lymphopaenia, LFTs, etc. De-risking strategies, e.g. JCV-testing

Anti-drug antibodies

Conclusion - mAbs