pegs m abs in rx ms
TRANSCRIPT
Overview on the Current Antibody Treatments for Multiple Sclerosis
Gavin Giovannoni
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
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
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
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
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
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
Natalizumab
Selewski . AJNR.2010
Natalizumab Efficacy
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
Global Natalizumab PML Incidence Estimates by Treatment Epoch: March 2016
Biogen Data on File, July 2016
Natalizumab PML risk stratification tool
www.ms-res.org
Determinants of survival in PML
Marzocchetti et al., Neurology 2009;73:1551–1558
Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function
Khatri et al. Neurology 2009;72:402–409
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.
Alemtuzumab
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.
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
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.
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
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
Daclizumab
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)
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
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
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
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)
*
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
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
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)
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
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
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
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
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
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
Ocrelizumab
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.
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
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
OCR Selectively Targets Mature B Cells While Sparing Other Immune CellsCytotoxic T cells
T helper cellsNatural Killer cells
CD19 B cells
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
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
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
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
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.
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.
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
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.
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
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
* 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
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)
Opicinumab
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.
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
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
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
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
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.
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