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This document provides an overview of current and emerging antibody treatments for multiple sclerosis (MS). It discusses approved therapies like natalizumab, alemtuzumab, and daclizumab. Natalizumab works by inhibiting lymphocyte binding to endothelial cells. Alemtuzumab depletes CD52+ lymphocytes. Daclizumab antagonizes CD25-mediated T cell activation. Emerging therapies discussed include ofatumumab, ustekinumab, and secukinumab which target CD20, IL-12/IL-23, and IL-17A respectively. The document also reviews the mechanisms of action, efficacy data, safety issues like PML risk, and ongoing clinical trials of these antibody treatments for MS.

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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-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
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
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
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
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 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
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.
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
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
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. 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)
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 CD56bright CD56bright 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 Median(±IQR)IL-2(pg/mL) Daclizumab 150mg (n=129) Placebo (n=38) *
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
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
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)
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
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
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
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
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
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 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.
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 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
OCR Selectively Targets Mature B Cells While Sparing Other Immune Cells Cytotoxic 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-1a p<0.0001 OPERA I OPERA II 47% ARR reduction vs IFN β-1a p<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 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
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-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
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.
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.
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
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.
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
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
* 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
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)
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-histamine 4. 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 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
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:P2.262 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
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
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 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

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Pegs m abs in rx ms

  • 1.
    Overview on theCurrent Antibody Treatments for Multiple Sclerosis Gavin Giovannoni
  • 2.
    Disclosures Over the last15 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-disablingdisease 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 therapiesfor 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 forMS 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 ProposedMOA 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 APCT 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.
  • 9.
  • 10.
  • 11.
    Kleinschmidt-DeMasters,et al. NEngl J Med. 2005 Jul 28;353(4):369-74. PML complicating treatment with natalizumab and IFNb-1a for MS
  • 12.
    Global Natalizumab PMLIncidence Estimates by Treatment Epoch: March 2016 Biogen Data on File, July 2016
  • 13.
    Natalizumab PML riskstratification tool www.ms-res.org
  • 14.
    Determinants of survivalin PML Marzocchetti et al., Neurology 2009;73:1551–1558
  • 15.
    Effect of plasmaexchange 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.
  • 18.
    Alemtuzumab: a humanizedmonoclonal 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 MSet 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-cellPharmacodynamics • 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: AlemtuzumabPharmacokinetics 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.
  • 24.
    MS treatments mostlyrely 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-2binding 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 actionof 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-2pathway 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 asustained 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 preventedIL-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: Annualisedrelapse 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 disabilityprogression *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 evidenceof 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 patientstreated 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 patientstreated 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 treatedwith 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.
  • 39.
    pro-B pre-B Stem cell Plasma cell (longlived) 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 expressdifferent 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 TargetsMature B Cells While Sparing Other Immune Cells Cytotoxic T cells T helper cellsNatural Killer cells CD19 B cells
  • 43.
    Reduction in ARRcompared 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 intotal 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 44μg (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 AEassociated 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 confirmeddisability 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 confirmeddisability 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 120during 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.
  • 56.
    Remyelination Nogo, MAG, OMgP Lingo-1-NgR-p75NTR GAP-43 NCAM Neuregulin Slidecourtesy 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 chronicMS 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 inremyelination 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 2study 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 atbaselinea 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 treatmentof 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