Professor Giovannoni Talk for PEG protein & Antibody Engineering Lisobon

1. Overview on the Current Antibody
Treatments for Multiple Sclerosis
Gavin Giovannoni

2. 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

3. 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

4. Approved disease-modifying therapies for MS
1994 1996 20001998 2002 2004 2006 2008 2010 2012 2014
SC IFN beta-1b
1995 (RMS)
IM IFN beta-1a
1997 (RMS)
SC IFN beta-1a
1998 (RMS)
Natalizumab
2006 (RRMS)
Glatiramer acetate
20 mg/mL
2003 (RMS)
Fingolimod
2011 (RRMS)
Alemtuzumab
2013 (RRMS)
Teriflunomide
2013 (RRMS)
2016
Dimethyl fumarate
2014 (RRMS)
Peginterferon beta-1a
2014 (RRMS)
Daclizumab
2016 (RMS)
Glatiramer acetate
40 mg/mL
2015 (RMS)
Ocrelizumab
2017 (RMS/PPMS)
Oral Cladribine
2017 (RMS/PPMS)
2018

5. Emerging therapies for MS
1994 1996 20001998 2002 2004 2006 2008 2010 2012 2014
SC IFN beta-1b
1995 (RMS)
IM IFN beta-1a
1997 (RMS)
SC IFN beta-1a
1998 (RMS)
Natalizumab
2006 (RRMS)
Glatiramer acetate
20 mg/mL
2003 (RMS)
Fingolimod
2011 (RRMS)
Alemtuzumab
2013 (RRMS)
Teriflunomide
2013 (RRMS)
2016
Dimethyl fumarate
2014 (RRMS)
Peginterferon beta-1a
2014 (RRMS)
Daclizumab
2016 (RMS)
Glatiramer acetate
40 mg/mL
2015 (RMS)
Ocrelizumab
2017 (RMS/PPMS)
Oral Cladribine
2017 (RMS/PPMS)
2018
Rituximab Ofatumumab

6. 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
mAbsinMS

7. Two compartment model
T
Te
B
APC T
Tc
Tc
Tc
Tc
B
Treg
BBB CNS
Bi
Te
Te
Bi
Te
Te
B
Treg Treg
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;9:125-6
1. Wiendl H, Kieseier B. Nat Rev Neurol. 2013;9:125-6
Intrathecal
immune
compartment

8. Natalizumab

9. Selewski . AJNR.2010

10. Natalizumab Efficacy

11. 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

12. Global Natalizumab PML Incidence Estimates by Treatment
Epoch: March 2016
Biogen Data on File, July 2016

13. Natalizumab PML risk stratification tool
www.ms-res.org

14. Determinants of survival in PML
Marzocchetti et al., Neurology 2009;73:1551–1558

15. Effect of plasma exchange in accelerating natalizumab
clearance and restoring leukocyte function
Khatri et al. Neurology 2009;72:402–409

16. 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.

17. Alemtuzumab

18. 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.

19. 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
CD52
T
T cell
precursor
Pre/Pro
B cell
B
CD52
T CD52
Monocytes
Macrophages
Neutrophils
Lymphocyte
precursor
Targets T and B cells thought to
mediate MS inflammation1
Lymphocyte
precursor
Lymphocyte
precursor
Stem cell

20. 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
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
Pre Post
(Day 2)
3 6 9 12 15 18
Months after Alemtuzumab (20 mg × 5)
Tcells
(×109/L)
0.0
0.1
0.2
0.3
0.4
0.5
Bcells
(×109/L)
B cells
CD4+ T cells
CD8+ T cells
Coles AJ et al. Lancet 1999;354:1691-5.

21. 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 dosing
Lycke J et al. EFNS 2012.
Alemtuzumab administration
1500
4000
4500
2500
3500
500
0
2000
3000
1000
Day 0
Concentration(ng/mL)
Day 5 Day 10 Day 15 Day 20 Day 25 Month 1
First treatment course
Time
1500
4000
4500
2500
3500
500
0
2000
3000
1000
0 1 3 6 9 12 2415 18 21
Concentration(ng/mL)
13
Months

22. CARE-MS II3,4
CARE-MS Extension: NEDA Through Year 5
Patients 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%)
ProportionofPatients,%(95%CI)
SC IFNB-1a 44 μg
Alemtuzumab 12 mg
SC IFNB-1a 44 μg
Alemtuzumab 12 mg
ProportionofPatients,%(95%CI)
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

23. Daclizumab

24. 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.
Alemtuzumab
CD52
Lysis of mature
B and T cells
Proposed MoA: Anti-migratory
Fingolimod
Natalizumab
Lymph node
BBB
CNS
S1P1
B
T
α4-integrin
Proposed MoA: Pleiotropic effects
Limits pyrimidine
availability for
rapid cell division
Teriflunomid
e
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 modulator
expands CD56-bright NK cells
Daclizumab (anti-CD25)

25. 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

26. 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

27. 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 CD56bright
CD56bright
CD56brightCD56bright
CD56bright
IL-2
IL-2 intermediate-affinity (βγ) receptor
IL-2 high-affinity (βαγ) receptor
Daclizumab

28. 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
Median(±IQR)IL-2(pg/mL)
Daclizumab 150mg (n=129)
Placebo (n=38)
*

29. CD25 blockade prevented IL-2 binding
but 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
Mo2.5
Mo4.5
Mo6.5–8.6
Mo10.5
Mo12.5–14.5
Absolutenumberofcellsperulofblood
IFN-β IFN-β
+dacliz daclizumab
0
2000
2500
500
Mo-3
Mo-1
Mo2.5
Mo4.5
Mo6.5–8.6
Mo10.5
Mo12.5–14.5
Absolutenumberofcellsperulofblood
IFN-β IFN-β
+dacliz daclizumab
1500
1000
CD56bright NK cells
0
200
250
50
Mo-3
Mo-1
Mo2.5
Mo4.5
Mo6.5–8.6
Mo10.5
Mo12.5–14.5
Absolutenumberofcellsperulofblood
IFN-β IFN-β
+dacliz daclizumab
1500
100

30. 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+ cells
1000
750
500
250
0
Baseline Week 24 Week 52
Mean(±SD)CD4+(cells/mm3)
800
600
400
200
0
Baseline Week 24 Week 52
Mean(±SD)CD8+(cells/mm3)
+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
0
Baseline Week 24 Week 52
Mean(±SD)
totallymphocytes(cells/mm3)
LLN

31. 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)
Daclizumab
150 mg
(n=201)
Daclizumab
300 mg
(n=203)
54%
relative
reduction
P<0.0001
50%
relative
reduction
P=0.00015
At Week 521,2 Up to Week 1442,3
IM IFN beta-1a
(n=922)
Daclizumab
150 mg
(n=919)
45%
relative
reduction
P<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
Annualisedrelapserate(95%
CI)
Annualisedrelapserate(95%
CI)

32. 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
196
201
192
198
183
190
171
185
167
184
114
132
0 12 24 36 48 60 72 84 96 108 120 132 144
27% relative risk reduction
HR=0.73 (95% CI: 0.55–0.98)
P=0.03
922
919
878
897
829
863
790
817
743
796
704
755
669
722
647
688
624
662
462
502
362
361
254
266
134
131
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 reduction
HR=0.24 (95% CI: 0.09–0.63)
P=0.0037
2.6%
11%
Up to Week 52* Up to Week 144†
No. at risk
Time on study (weeks) No. at risk
Patientswithconfirmed
disabilityprogression
(%)
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

33. 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
PatientsachievingNEDA
(%)
OR: 2.96
P<0.0001
IM IFN beta-1a
Daclizumab
n=347/77
6
n=173/77
3
n=367/88
4
n=282/86
4
EDSS
Brain
MRI
✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓
0 12 24 36 48 60 72 84 96-144
OR: 1.51
P<0.0001

34. 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 treatment1,4
• Most elevations were asymptomatic and resolved spontaneously3,4
• In DECIDE median (25th–75th percentiles) duration of ALT or AST elevation >5× ULN
was 87.0 (50.0–128.0) days in daclizumab group vs 100.0 (75.5–136.5) in IM IFN beta-1a4
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 16
Serious hepatic events, % <1 <1 1
ALT or AST, %
≥3× ULN 9 9 10
>5× ULN 6 3 6
Discontinuation due to hepatic events, % 5 4 5

35. 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 mg
n=1943
IM IFN beta-1a
n=922
Daclizumab 150 mg
n=919
Skin reactions, % 32 19 37
Serious skin reactions, % 2 <1 2
Discontinuation 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

36. 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 mg
n=1943
IM IFN beta-1a
n=922
Daclizumab 150 mg
n=919
Infections, % 58 57 65
Serious 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 groups3
• Majority of patients with infections continued on treatment (discontinuation due to infections <1%)3

37. 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

38. Ocrelizumab

39. pro-B
pre-B
Stem cell
Plasma cell
(long lived)
Mature naive
B cell
Activated
B cell
Lymph follicle
with germinal center
Plasmablast Memory
B cell
Follicle-like
aggregates
Bystander
activation
Plasma cell
(long lived)
OCB
CNS Educated B cells CSF
Dendritic
Cell
T cell
B cells and the brain
Plasmablast
Bone Marrow Central Nervous SystemSecondary Lymphoid TissuesCNS, central nervous system; CSF, cerebrospinal fluid; OCB, oligoclonal band.

40. 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

41. 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 interactor
Image 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
CD52
CD138
a4-INTEGRIN
BAFF-R
BCMA
TACI
B cell reconstitution
preserved1-3
Long-term memory
preserved1,2,4

42. OCR Selectively Targets Mature B Cells While Sparing Other Immune Cells
Cytotoxic T cells
T helper cellsNatural Killer cells
CD19 B cells

43. 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-1a
p<0.0001
OPERA I OPERA II
47%
ARR reduction
vs IFN β-1a
p<0.0001

44. 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
ITT
CDP, confirmed disability progression; CI, confidence interval; HR, hazard ratio; IFN, interferon; OCR, ocrelizumab
15.2
9.8
12.0
7.6
Reduction in pre-specified pooled analysis of confirmed
disability progression (CDP) at 12 and 24 weeks

45. 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

46. 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-1a
p<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

47. n (%)
IFN β-1a
44 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 Complications
Infusion-related reaction
General Disorders and Administration-site Conditions
Influenza-like illness
Injection-site erythema
Fatigue
Injection-site reaction
Infections and Infestations
Upper respiratory tract infection
Nasopharyngitis
Urinary tract infection
Sinusitis
Bronchitis
Nervous System Disorders
Headache
Psychiatric Disorders
Depression
Insomnia
Musculoskeletal and Connective Tissue Disorders
Back pain
Arthralgia
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.

48. 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-1a
44 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.

49. 1.4
0.5
1.5
0.5
1.7
0.95.1
1.3
0.1
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 4Dose 1 Dose 2 Dose 3 Dose 4
1.0
0.1 3.6
1.1
6.0
1.8
10.8
2.6
0.4
7.4
1.8
0.4
18.3
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 2Infusion 1 Infusion 2

50. ORATORIO PPMS
50
Confidential — For internal use only. Do not
copy, distribute or use without prior written
consent
Placebo
n=244
Ocrelizumab
600 mg
n=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 findings
Gd– 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.

51. 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 age
Patients with initial disability progression who discontinued treatment early with no confirmatory EDSS assessment were considered as having confirmed disability progression

52. 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 age
Patients with initial disability progression who discontinued treatment early with no confirmatory EDSS assessment were considered as having confirmed disability progression

53. * Week 120 during the Double-Blind Treatment Period (ranked ANCOVA, MMRM)
10%
change in 25-foot walk
vs. placebo
p=0.404
Reduction in rate of decline in walking speed

54. Deaths and Malignancies
54
n (%)
Placebo
n=239
Ocrelizumab
600 mg
n=486
Deaths
1 (0.4)
Road traffic accident
Sudden cardiac death
Aspiration
4 (0.8)
Pulmonary embolism
Pneumonia
Pancreas 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)

55. Opicinumab

56. 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-histamine
4. IRX4204 & Bexarotene: RXR-agonist
5. Etc.

57. Premyelinating oligodendrocytes
in chronic MS lesions1
Negative regulators of OPC differentiation have been
identified2,3
Investigating LINGO-1 as a target for remyelination
and 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 RNAi
In vitro effects of LINGO-1 blockade4
Mature
oligodendrocyte
OPCs
Differentiation
LINGO-1,
PSA-NCAM, Notch
Anti-LINGO-1
treatment
Proximal Distal
Control
treatment
Fluorescein isothiocyanate-conjugated cholera
toxin B–labeled axons after optic nerve crush
and vehicle injection

58. 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

59. New phase 2 study designs: Acute optic neuritis
to assess neuroprotection and remyelination
1. Cadavid D et al. Presented at AAN; Philadelphia, USA; 2014:P2.262
2. 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 period
20 weeks
Assessments at
24 and 32 weeks
3–5 days’
IV steroids
End of study
follow-up
32 weeks
Primary outcome: VEP

60. 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
0
PP ITT
22.24
14.69
20.83
17.34
Week 24
34%
Latency
recovery
P=0.05
17%
Latency
recovery
P=0.33
Adjustedmean
changein
Full-fieldVEP
latency*(ms)
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 32
41%
Latency
recovery
P=0.01
29%
Latency
recovery
P=0.07
n=36 n=33 n=41 n=41

61. 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.

62. Revolutionised the treatment of MS
Targeted therapies
Better outcomes
Complex biology
New insights
Anti-trafficking - rebound/IRIS
Challenging dogmas
T-cell vs. B-cells
CD56-bright NK cells
Secondary autoimmunity
Better outcomes, but more risk
Increased monitoring requirement, e.g. lymphopaenia, LFTs, etc.
De-risking strategies, e.g. JCV-testing
Anti-drug antibodies
Conclusion - mAbs