Léky druhé linie Eva Kubala Havrdová

Cíl léčby: koncept NEDA no evidence of disease activity Poprvé použito při zhodnocení klinické studie s natalizumabem AFFIRM (post hoc analýza 2007) Do té doby byla spokojenost se snížením počtu relapsů Nikdo neočekával, že by bylo možné docílit zastavení progrese RS či zlepšení klinického nálezu

Můžeme ignorovat relapsy? Ebers: Relapsy nejsou důležité pro prognózu RS, pouze jejich počet v prvých dvou letech Lublin: Následky relapsů jsou odpovědné za 42 % disability Lublin. J Neu Sci 2007;256:S14-18

NEDA 3 Podobné dlouhodobé remisi v onkologii či revmatologii Is it heavily biased towards MRI? Havrdová E et al. Lancet Neurol 2009

Ambicioznější cíl: NEDA 3  4 WHY? MRI is the only window we can use to look directly at patological processes in MS Biochemical biomarkers not yet agreed OCBs – prediction f CIS into MS conversion Neurofilaments – prediction of disability (?), correlation with tissue destruction Mezi invaliditou a atrofií mozku u RS je prokázaná korelace

Proč potřebujeme léky 2. linie? Léčba léky 1. volby u remitentní RS v dlouhodobém horizontu: 62% - 75% pac. relabuje během 2 let 20% - 27% pac. se zhorší o ≥1 bod EDSS během 2 let 38% - 45% neléčených pacientů s CIS vyvine CDMS (další ataku nebo zhoršení EDSS) během 2 let

Lze docílit NEDA – 3 injekčními léky? Indirect evidence Tx naive Switch within injectables 1. Cohen et al. Lancet. 2012 Nov 24;380(9856):1819-28 2. Coles et al. Lancet. 2012 Nov 24;380(9856):1829-39. 7

Počet pacientů s NEDA se během doby snižuje SET Study 210 CIS pts (MRI + OCBs pos.) All started IFNB-1a i.m. within 4 months from symptoms onset Uher T et al. Mult Scler 2016 May 26, pii 1352458516650525

Co dělat? Pokud necháme pacienta na neúčinné léčbě, směřuje do neodvratné invalidity Metodou volby je eskalace léčby Účinnější léky spojeny s vyšším rizikem Praxe v ČR se zatím liší od SPC přípravků i od mezinárodních guidelines !

Po jedné atace… DMF, fingolimod Mimo ČR: všude dimethyl fumarát lék první volby USA, Austrálie, Švýcarsko: fingolimod lékem první volby

Mechanismus účinku DMF

Fumarát: Snížení výskytu relapsů po 2 letech léčby versus placebo (DEFINE Study) ARR vypočtena pomocí negativní binomiální regrese, s úpravou podle počátečního skóre EDSS (≤2,0 vs. >2,0), počátečního věku (<40 vs. ≥40 let), regionu a počtu relapsů během 1 roku před vstupem do studie. Gold R et al. Placebo-Controlled Phase 3 Study of Oral BG-12 for Relapsing Multiple Sclerosis. N Engl J Med 2012;367:1097-1107

Fumarát: Snížení rizika progrese disability přetrvávající po dobu 12 týdnů Doba do potvrzení progrese postižení o délce 12 týdnů (sekundární parametr) Pacienti byli cenzurováni, pokud ze studie vystoupili nebo přešli na alternativní medikaci RS bez progrese. Gold R et al. Placebo-Controlled Phase 3 Study of Oral BG-12 for Relapsing Multiple Sclerosis. N Engl J Med 2012;367:1097-1107

NEDA u DMF

Co monitorujeme? Krevní obraz – snížení počtu lymfocytů pod 500 může ohrozit pacienta rizikem PML Jaterní testy Zažívací obtíže (nausea, křeče v břiše, průjem) Rudnutí na 15-30 minut po dávce (někdy pomáhá Zyrtec)

Fingolimod

Fingolimod: klinické studie: relapsy

Fingolimod: klinické studie: progrese disability

Fingolimod: klinické studie: MRI

Data o atrofii mozku z klinických studií svědčí o neuroprotektivním působení fingolimodu (2-letá data studie FREEDOMS) Time (months) 6 12 24 0.0 ** -0.4 * Fingolimod 0.5 mg Časný a trvalý vliv na vývoj atrofie mozku *** -0.8 Placebo Change in mean BV from baseline (%) -1.2 -1.6 Overall study population -2.0 38% redukce postupu ztráty mozkové tkáně u fingolimodu 0,5 mg vs placebo *p<0.05, **p<0.01, ***p<0.001 vs placebo; p-values are for comparisons over Months 0-6, Months 0-12, Months 0-24; patient numbers at baseline were 425 and 418 for fingolimod 0.5 mg and placebo, respectively. BV, brain volume Radue E et al. Poster P05.064 presented at AAN 2011; Gilenya™ Summary of Product Characteristics, 4 April 2011

Data o atrofii mozku z klinických studií svědčí o neuroprotektivním působení fingolimodu (2-letá data studie FREEDOMS) 6 12 24 Time (months) 0.0 Gd-enhancing lesions at baseline -0.4 Fingolimod 0.5 mg -0.8 Change in mean BV from baseline (%) Placebo -1.2 * -1.2 -1.6 -1.6 -2.0 -2.0 Time (months) 6 12 24 0.0 Rychlost ztráty mozkového objemu je nižší na fingolimodu 0,5mg oproti placebu, efekt je patrný již v 6 měsících léčby, je setrvalý po celou dobu studie (2 roky) a je nezávislý na míře zánětu -0.4 ** * † -0.8 Change in mean BV from baseline (%) -1.2 -1.6 No Gd-enhancing lesions at baseline -2.0 *p<0.05, **p<0.01, ***p<0.001 vs placebo; †p = 0.061 vs placebo; p-values are for comparisons over Months 0-6, Months 0-12, Months 0-24; patient numbers at baseline were 425 (n = 161 with Gd-enhancing lesions; n = 263 without Gd-enhancing lesions) and 418 (n = 154; n = 262) for fingolimod 0.5 mg and placebo, respectively; Gd, gadolinium; Radue E et al. Poster P05.064 presented at AAN 2011

Fingolimod a NEDA NEDA-3 NEDA-4 ® OR 4.07 p<0.0001 Patients achieving NEDA (%) ® OR 4.41 p<0.0001 Patients achieving NEDA (%) Kappos, L, et al. Presented at ECTRIMS 2014, 10-13 September. Boston, USA (Presentation FC1.5)

Bezpečnost – co monitorujeme?  zvýšení jaterních testů  Redukce v bílém krevním obraze (lymfocyty a celk. WBC) – = očekávaný farmakodynamický efekt spíš než NÚ  Bradykardie – transientní, při začátku léčby (1. den, monitorace 6h, možnost AV bloku)  Makulární edém  Hypertenze  Dyspnea  Infekce: dolní respirační trakt, herpetické infekce (2 úmrtí) – nutné testovat protilátky proti VZV před zahájením léčby Teratogenicita

Natalizumab Adhezivní molekuly hrají základní roli v přestupu lymfocytů do tkáně

Annualized Relapse Rate (95% CI) Natalizumab: AFFIRM: Roční relaps rate Primary Endpoint pro 1. rok Placebo n=315 0.78 0.68 0.73 0.27 0.20 0.24 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Over 1 Year 1-2 Years Over 2 Years Annualized Relapse Rate (95% CI) Natalizumab n=627 P<0.0001 P<0.0001 P<0.0001 66% 68% 71% FDA per subject mean relapse rate at 2 years = 0.67 for placebo and 0.22 for natalizumab (67% reduction)

Mean No. of New or Enlarging T2 Lesions Počet nových a zvětšujících se T2 lézí Placebo n=315 P<0.0001 Natalizumab n=627 12 11.0 10 P<0.0001 8 6.1 P<0.0001 83% Mean No. of New or Enlarging T2 Lesions 6 4.9 4 80% 86% 1.9 2 1.2 0.7 Year 0–1 Year 1–2 Year 0–2

Cumulative Probability Doba od první infuze natalizumabu do progrese či zlepšení v reálné praxi (při eskalaci) 1.00 0.90 Progression Improvement 0.80 ZLEPŠENÍ neurologckého nálezu 0.70 0.60 Cumulative Probability 0.50 0.40 0.30 19% 0.20 0.10 11% 12 24 36 48 60 72 84 96 108 120 132 144 Weeks from First Natalizumab Infusion Number of Patients at Risk Improvement Progression 3472 3472 2576 2607 1734 1890 1060 1177 597 672 365 391 183 193 *Sustained (6-month) progression was defined as a ≥1.0-point increase in EDSS score from baseline. †Sustained (6-month) improvement was defined as a ≥1.0-point decrease in EDSS score from baseline.

Vliv pozdní eskalace léčby TOP (Tysabri Observational Program) Vývoj EDSS (Patienti s ročními daty) CR: p=0.4788* Global: p<0.0001 ČR ČR N(CR)=92* N(Global)=1532 * Data Export Date 01JUN2011 (Czech)

Progresivní multifokální leukoencefalopatie Závažná komplikace léčby natalizumabem Podmínky: přítomnost JC viru v organizmu a jeho mutace (neumíme detekovat) Léčba natalizumabem přesahující 18 měsíců

příčina: JC virus (40nm, DNA polioma virus) Výskyt PML : imunokompromitovaný pacient HIV+ (5% pacientů), malignity, transplantace kde se bere JC virus : v ledvinách a kostní dřeni 50-60% zdravých osob – inapar. infekt během dětství Klinický obraz : kognitivní porucha (49%) motorické příznaky (37%) dysarthrie, afazie (31%) vizuální poruchy (29%) ataxie 17%, ep 17%

PML K 7.12.2017 bylo 756 případů PML (>177800 léčených pacientů natalizumabem) PML se objevila za 8 –136 měsíců léčby (v průměru 49 m) Přežilo 76,4% pacientů Různé stupně postižení

Diagnostika Každá nová “ataka” na natalizumabu je podezřelá z PML – STOP natalizumab Klinické příznaky (většinou nerozpoznatelné od RS) MR (často nutno opakovat) CSF – vyšetření DNA JC viru Informace o předchozí imunosupresi! Při nevyjasněné dg. nelze podat další natalizumab, vyšetření je nutno opakovat

IRIS Inflamatorní rekonstituční imunitní syndrom Imunitní systém se snaží s infekcí bojovat – vtrhne do CNS Příznaky se zhorší, může se objevit horečka, porucha vědomí, zhoršení nálezu na MR Neléčený může vést ke smrti

Léčba PML (dg. potvrzená MRI a CSF) Vysazení natalizumabu (5x plazmaferéza) ??? Léčba IRIS kortikosteroidy rehabilitace Outcome: 24 % mortalita (RS) Invalidita u přeživších: 10 % lehká, 50 % střední, 40 % těžká

Riziko PML Dříve udávané 1:1000 pacientů Rizikové faktory: JCV Ab+, léčb nad 2 roky, předchoz imunosuprese Nyní: u JCV negativních riziko existuje, u JCV pozitivních bez předchozí imunosuprese záleží na titru protilátek (antibody index) Infekci můžeme získat I v dospělosti JCV + je kolem 60% zdravé populace Riziko musí být s pacientem kommunikováno

Kumulativní riziko PML podle délky trvání léčby

Bezpečnostní opatření - farmakovigilance Výběr pacientů, MR před zahájením léčby Diskuse o riziku v průběhu léčby Dotazník před každou infuzí Vyšetřování AI Pravidelné MR (od 18. měsíce a 3 měsíce tzv. krátký FLAIR), protože dg. na MR předchází klinickým příznakům a má o něco lepší prognózu) Nové příznaky považovat za podezřelé z PML

Alemtuzumab – monoklonální protilátka proti CD52

Alemtuzumab: co se stane s buňkami MOA Alemtuzumab: co se stane s buňkami Hu/2009//p260/col1/para1; Fox/2010/p1790/col1/para4; White Blood Cell Counts: CARE-MS I6 Neutrophils Monocytes Eosinophils Basophils Lymphocytes 0.0 0.5 1.0 1.5 2.0 4.0 4.5 5.0 1 2 3 4 5 6 7 8 9 10 11 12 Cell Counts (109/L) Months after Alemtuzumab Coles/2010/AAN/col2/fig1a Alemtuzumab působí depleci cirkulujících B a T lymfocytů, tedy akutní protizánětlivý efekt Lymfocytární repopulace začíná ihned a probíhá dlouho1 Preklinické studie ukazují, že lymfocyty jsou i nadále v lymfatických orgánech,2,3 mají normální funkci,4,5 a že vývoj imunitní odpovědi je jen minimálně ovlivněn4,5 Alemtuzumab má minimální vliv na buňky vrozené imunity1-3 Hu/2009//p264/col1/para2; Coles/1999/p1692/Col2/para4 Coles/2006/p104/col2/para2 Coles/2010/AAN/col2/fig1b Coles/2010/AAN/col1/results&fig1a&1b&summary; Cox/2005/p3333/col2/Fig1a,1b$1d · remaining immune cells retain normal function. Turner et al., ECTRIMS 2011 + Siders et al., Keystone 2011 · Many lymphocytes are still present in lymphoid organs (hu et al paper) Hu et al enclosed + Turner et al AAN 2009 · development of immune responses is minimally impacted Siders et al., Keystone 2011 for acquired immune responses (B and T cells) and Turner et al., ECTRIMS 2011 for innate immune responses 1. Coles AJ et al. AAN 2010, poster P06.172; 2. Hu Y et al. Immunology 2009;128:260–270; 3. Turner MJ et al. AAN 2010, poster P06.207; 4. Turner MJ et al. ECTRIMS 2011, poster 791; 5. Siders WM et al. Keystone 2011; 6. CARE-MS I Clinical Study Report (data on file, Genzyme Corporation) 43

CARE-MS I a II: Roční výskyt relapsů CARE-MS II Rate reduction: 54.9% p<0.0001 Rate reduction: 49.4% p<0.0001 SC IFN β-1a 44 μg Alem 12 mg Adjusted ARR (95% CI) Adjusted ARR (95% CI) The annualized relapse rate was significantly lower with alemtuzumab vs. SC IFN β-1a (p<0.0001), in both CARE-MS I and II: 54.9% reduction in CARE-MS I 49.4% reduction in CARE-MS II 0.39 0.18 0.52 0.26 Years 0–2 Years 0–2 ARR, annualized relapse rate; CI confidence interval. 1. Cohen JA et al, Lancet 2012; 380:1819-28; 2. Coles JA et al. Lancet 2012;380:1829-39.

CARE-MS I a II: Doba do zhoršení disability (SAD) trvající 6 měsíců CARE-MS II SC IFN β-1a Alem 12 mg SC IFN β-1a Alem 12 mg HR: 0.70 p=0.22 HR: 0.58 p=0.0084 21.1% 11% Percentage of Patients with SAD Percentage of Patients with SAD 8% 12.7% 3 6 9 12 15 18 21 24 CARE-MS II: Proportion of patients with 6-month SAD at Year 2 was significantly lower with alemtuzumab vs. SC IFN β-1a (12.7 vs. 21.1%, representing a 42% decreased risk: HR=0.58, p=0.0084) CARE-MS I: Although the proportion of patients with 6-month SAD at Year 2 was numerically lower with alemtuzumab vs. SC IFN β-1a, this between-treatment difference was not statistically significant. The study had been powered assuming a 20% SAD rate in the INF β arm based on CAMMS223 and other studies. Fewer (11%) IFN β-1a patients accumulated disability than expected from previous clinical trials, which may have reduced the ability to detect a significant treatment effect Follow-up Month Follow-up Month No significant difference between treatments on EDSS-based endpoints in CARE-MS I A 42% decreased risk of sustained accumulation of disability in CARE-MS II SAD defined as a ≥1 point increase in EDSS lasting ≥6 months (or ≥1.5 point increase if baseline EDSS=0) HR, hazard ratio; SAD, sustained accumulation of disability. 1. Cohen JA et al, Lancet 2012; 380:1819-28; 2. Coles JA et al. Lancet 2012;380:1829-39. 45 45

Alemtuzumab: zlepšení neurologického nálezu Figure 7. Time to 6-month SRD HR=hazard ratio Follow-up Month 12.9% 28.8% HR=2.57 p=0.0002 SC IFNB-1a Alem 12 mg 40 30 20 10 3 6 9 12 15 18 21 24 Patients with SRD, % 153 151 142 137 129 122 117 114 107 321 290 275 262 254 245 235 213 No. at Risk Figure 6. Time to 3-month SRD HR=2.13 p=0.0003 138 133 123 110 105 99 280 261 241 233 222 194 19.4% 34.7%

CARE-MS I a II: Pacienti s dlouhodobou remisí CARE-MS II OR: 1.75 p=0.0084 OR: 3.03 p<0.0001 59.6 41.1 Patients (%) Patients (%) A significantly greater proportion of patients were disease-free in Years 1 and 2 with alemtuzumab vs. SC IFN β-1a in both studies SC IFN β-1a 44 μg Alem 12 mg/ MS disease activity-free: clinical disease activity-free (defined as absence of relapse and sustained disability progression) and MRI activity-free (defined as absence of new Gd-enhancing lesion and new or enlarging T2 hyperintense lesions). 1. Giovannoni G et al. Oral presentation at ENS 2012; Hartung HP et al. Poster 07.093 presented at AAN 2013

Rate of Brain Volume Loss Slowed Over 5 Years in Patients Receiving Only the Initial 2 Courses of Alemtuzumab AAN 2016 Percentage BVL From Baseline Median Annual Brain Volume Change Alemtuzumab 12 mg (no retreatment or other DMT) Year Median Change From Baseline, % (95% CI) Alemtuzumab 12 mg (no retreatment or other DMT) t_1_04_tex1_mri_bpf_pooled_retrt Year Core Studies Extension Study Core Studies Extension Study No. of Patients No. of Patients 432 429 407 378 358 438 432 430 407 384 373 Median yearly BVL progressively decreased over 3 years and remained low in Years 4 and 5 BVL=brain volume loss.

Identifikovaná rizika Strategie jejich zmírnění Identifikovaná rizika a strategie k jejich omezení, která se formovala během klinického vývoje alemtuzumabu Identifikovaná rizika Strategie jejich zmírnění IAR Infekce Onemocnění štítné žlázy ITP Nefropatie

Ocrelizumab Humanizovaná protilátka proti CD20, znaku B lymfocytů Rituximab se již řadu let ve studiích nepoužívá, přestože použití u PP RS ukázalo, že mladší pacienti s aktivitou choroby profitují V klinické praxi se rituximab nadále používá jak u RS tak u NMO Především jako přechod z natalizumabu při vysokém riziku PML

Role B lymfocytů v patogeneze RS Cytokine production2,3 Antigen presentation1,2 Autoantibody production4 B cells may influence the underlying pathophysiology of MS through at least four specific functions: Antigen presentation: B cells can present self neuroantigens to T cells and activate them1,2 Cytokine production: B cells in patients with MS produce abnormal proinflammatory cytokines, which can activate T cells and other immune cells2,3 Autoantibody production: B cells produce autoantibodies that may cause tissue damage and activate macrophages and natural killer (NK) cells4 Follicle-like aggregate formation: B cells are present in ectopic lymphoid follicle-like aggregates, linked to microglia activation, local inflammation, and neuronal loss in the nearby cortex5,6 References: 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 CZ/NEUR/0217/0008 1. Crawford A, et al. J Immunol 2006;176(6):3498–506. 2. Bar-Or A, et al. Ann Neurol 2010;67(4):452–6. 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.

Likvidace CD20+ B lymfocytů COMPLEMENT-DEPENDENT CYTOTOXICITY1-3 DIRECT APOPTOSIS1-3 ANTIBODY-DEPENDENT CELLULAR CYTOTOXICITY1-3 Ocrelizumab binds to the large extracellular loop of CD20 and is characterised as a Type I antibody1 After binding to CD20+ cells, ocrelizumab may potentially mediate lysis of CD20-expressing B cells through2: Antibody-dependent cellular cytotoxicity (ADCC): a form of cell-mediated cytotoxicity in which an effector cell (e.g., NK cell) engages an antibody-coated target cell and actively lyses the target Antibody-dependent cellular phagocytosis (ADCP): a form of cell-mediated cytotoxicity used primarily by macrophages to engulf and degrade antibody-coated target cells Complement-dependent cytotoxicity (CDC): cell-killing mediated by the complement cascade. Antibody binding triggers formation of the membrane attack complex (MAC) that can directly induce B-cell lysis Apoptosis: direct cellular cytotoxicity with a cross-linking antibody Of these mechanisms, ADCC and CDC may be most important References: 1. Klein C, et al. MAbs 2013;5(1):22–33. 2. Jaglowski SM, et al. Blood 2010;116(19):3705–14. ANTIBODY-DEPENDENT CELLULAR PHAGOCYTOSIS1-3 1. Jaglowski SM, et al. Blood 2010;116(19):3705–14. 2. Winiarska M, et al. Front Biosci 2011;16:277–306. 3. Klein C, et al. MAbs 2013;5(1):22–33.

ARR reduction vs. IFN β-1a OPERA I and OPERA II Primary Endpoint: Protocol-defined ARR at 96 Weeks OPERA I OPERA II 46% ARR reduction vs. IFN β-1a p<0.0001 47% ARR reduction vs. IFN β-1a p<0.0001 CZ/NEUR/0217/0008 ITT = intent to treat *Adjusted ARR calculated by negative binomial regression and adjusted for baseline EDSS score (<4.0 vs. ≥4.0), and geographic region (United States vs. ROW). Hauser SL, et al. ECTRIMS 2015; 7-10 October 2015, Barcelona, Spain. Platform presentation 190. Důvěrné

Risk reduction: 40% HR (95% CI): 0.60 (0.45, 0.81); p=0.0006 OPERA I and OPERA II Prespecified Pooled Secondary Endpoint: Time to Onset of CDP for at Least 12 Weeks 15.2 9.8 Risk reduction: 40% HR (95% CI): 0.60 (0.45, 0.81); p=0.0006 IFN β-1a 828 784 741 696 665 632 608 583 449 OCR 600 mg 827 795 765 737 716 702 688 672 526 N CZ/NEUR/0217/0008 ITT CDP, confirmed disability progression; CI, confidence interval; HR, hazard ratio; IFN, interferon; OCR, ocrelizumab Hauser SL, et al. ECTRIMS 2015; 7-10 October 2015, Barcelona, Spain. Platform presentation 190. Důvěrné

OPERA I and OPERA II Secondary Endpoint: Time to Onset of CDP for at Least 12 Weeks 17.5 13.0 11.1 8.3 Risk reduction: 43% HR (95% CI): 0.57 (0.37, 0.90); p=0.0139 Risk reduction: 37% HR (95% CI): 0.63 (0.42, 0.92); p=0.0169 n IFN β-1a 410 395 369 352 341 328 319 306 245 OCR 391 380 363 358 351 348 280 n IFN β-1a 418 389 372 344 324 304 289 277 204 OCR 417 404 385 368 353 337 246 CZ/NEUR/0217/0008 ITT CDP, confirmed disability progression; CI, confidence interval; HR, hazard ratio; IFN, interferon; OCR, ocrelizumab Hauser SL, et al. ECTRIMS 2015; 7-10 October 2015, Barcelona, Spain. Platform presentation 190. Důvěrné

Risk reduction: 40% HR (95% CI): 0.60 (0.43, 0.84); p=0.0025 OPERA I and OPERA II Prespecified Pooled Secondary Endpoint: Time to Onset of CDP for at Least 24 Weeks 12.0 7.6 Risk reduction: 40% HR (95% CI): 0.60 (0.43, 0.84); p=0.0025 IFN β-1a 828 785 747 705 677 644 622 600 466 OCR 600 mg 827 797 772 748 731 717 704 688 540 N CZ/NEUR/0217/0008 ITT CDP, confirmed disability progression; CI, confidence interval; HR, hazard ratio; IFN, interferon; OCR, ocrelizumab Hauser SL, et al. ECTRIMS 2015; 7-10 October 2015, Barcelona, Spain. Platform presentation 190. Důvěrné

OPERA I and OPERA II Secondary Endpoints: Time to Onset of CDP for at Least 24 Weeks 13.6 10.6 8.6 6.5 Risk reduction: 43% HR (95% CI): 0.57 (0.34, 0.95); p=0.0278 Risk reduction: 37% HR (95% CI): 0.63 (0.40, 0.98); p=0.0370 n IFN β-1a 411 395 371 356 347 334 323 310 252 OCR 410 392 382 373 369 363 357 354 284 n IFN β-1a 418 390 376 349 330 310 299 290 214 OCR 417 405 375 362 354 347 334 256 CZ/NEUR/0217/0008 ITT CDP, confirmed disability progression; CI, confidence interval; HR, hazard ratio; IFN, interferon; OCR, ocrelizumab Hauser SL, et al. ECTRIMS 2015; 7-10 October 2015, Barcelona, Spain. Platform presentation 190. Důvěrné

OPERA I and OPERA II Secondary Endpoint: Number of T1 Gd-Enhancing Lesions per MRI Scan Collected at Weeks 24, 48, and 96 OPERA II OPERA I 94% Reduction vs. IFN β-1a p<0.0001 95% Reduction vs. IFN β-1a p<0.0001 A comment to presenters: scale of graphs may lead to misleading impression. The X axis scale should be emphasised given the large bars visually. Notes from Fabian: our endpoint for all lesion counts is the lesion rate per MRI scan.   Per treatment arm we report the adjusted lesion rates per MRI scan, the treatment effect is the adjusted lesion rate ratio.  In principle the lesion rate per MRI scan is simply the total number of lesions divided by the total number of MRI scans (across patients and visits) - this is the so called crude or unadjusted rate. You could also describe it as the mean number of lesions per MRI scan. The "adjusted" means that we take individual patient characteristics that impact the risk of developing a lesion into account when estimating the rates and the rate ratio. The analysis is basically identical to our primary endpoint: relapse rate per year. Annualised Relapse Rate (ARR) is the average number of relapses per year, our lesion rates are the average number of lesions per MRI scan. Some more nuances: - we only use scheduled visits for analysis - assumptions the analysis is based on:     + the expected number of new lesions after 24 weeks (BL-24, 24-48) and after 48 weeks (48-96) is identical    + the treatment effect (reduction in lesion rate) is identical at 24, 48 and 96 weeks    + these assumptions are identical to the more classical analysis of just summing up the number of lesions across visits with the advantage that no imputation of missing MRI scans needs to be performed CZ/NEUR/0217/0008 ITT *Adjusted by baseline T1 Gd lesion (present or not), baseline EDSS (<4.0 vs. ≥4.0) and geographic region (US vs. ROW). Hauser SL, et al. ECTRIMS 2015; 7-10 October 2015, Barcelona, Spain. Platform presentation 190. Důvěrné

Exploratory endpoint: Reduction in mean T1 Gd+ lesions compared with IFN β-1a from podium talk OPERA I OPERA II 97% p<0.0001 95% p<0.0001 96% p<0.0001 92% p<0.0001 98% p<0.0001 From: t_mri_t1gd_IT_092_0.2, t_mri_t1gd_nbino_vis_IT_092, t_mri_t1gd_IT_093_0.1, t_mri_t1gd_nbino_vis_IT_093 91% p<0.0001 n IFN β-1a 372 357 335 Ocrelizumab 382 377 359 n IFN β-1a 372 334 311 Ocrelizumab 385 373 359 CZ/NEUR/0217/0008 ITT *Adjusted by means calculated by negative binomial regression and adjusted for baseline T1 Gd lesion (present or not), baseline EDSS (<4.0 vs ≥4.0) and geographical region (US vs ROW). EDSS, Expanded Disability Status Scale; Gd+, gadolinium enhancing; IFN, interferon; MRI, magnetic resonance imaging; ROW, rest of the world. Hauser SL, et al. ECTRIMS 2015; 7-10 October 2015, Barcelona, Spain. Platform presentation 190. Důvěrné

OPERA I and OPERA II Secondary Endpoint: Total Number of New or Enlarging T2 Hyperintense Lesions per MRI Scan at Weeks 24, 48, and 96 OPERA I OPERA II 77% Reduction vs. IFN β-1a p<0.0001 83% Reduction vs. IFN β-1a p<0.0001 Notes from Fabian: our endpoint for all lesion counts is the lesion rate per MRI scan.   Per treatment arm we report the adjusted lesion rates per MRI scan, the treatment effect is the adjusted lesion rate ratio.  In principle the lesion rate per MRI scan is simply the total number of lesions divided by the total number of MRI scans (across patients and visits) - this is the so called crude or unadjusted rate. You could also describe it as the mean number of lesions per MRI scan. The "adjusted" means that we take individual patient characteristics that impact the risk of developing a lesion into account when estimating the rates and the rate ratio. The analysis is basically identical to our primary endpoint: relapse rate per year. Annualised Relapse Rate (ARR) is the average number of relapses per year, our lesion rates are the average number of lesions per MRI scan. Some more nuances: - we only use scheduled visits for analysis - assumptions the analysis is based on:     + the expected number of new lesions after 24 weeks (BL-24, 24-48) and after 48 weeks (48-96) is identical    + the treatment effect (reduction in lesion rate) is identical at 24, 48 and 96 weeks    + these assumptions are identical to the more classical analysis of just summing up the number of lesions across visits with the advantage that no imputation of missing MRI scans needs to be performed CZ/NEUR/0217/0008 ITT *Adjusted by means calculated by negative binomial regression and adjusted for 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. Hauser SL, et al. ECTRIMS 2015; 7-10 October 2015, Barcelona, Spain. Platform presentation 190. Důvěrné

Exploratory endpoint: Reduction in total new and/or enlarging T2 hyperintense lesions compared with IFN β-1a OPERA I OPERA II 97% p<0.0001 98% p<0.0001 61% p<0.0001 41% p=0.0002 96% p<0.0001 94% p<0.0001 From: t_mri_t2ne_IT_092_0.2, t_mri_t2ne_nbino_vis_IT_092, t_mri_t2ne_IT_093_0.1, t_mri_t2ne_nbino_vis_IT_093 n IFN β-1a 373 357 336 Ocrelizumab 385 378 360 n IFN β-1a 374 337 314 Ocrelizumab 387 376 360 CZ/NEUR/0217/0008 ITT *Adjusted by means calculated by negative binomial regression and adjusted for 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. Hauser SL, et al. ECTRIMS 2015; 7-10 October 2015, Barcelona, Spain. Platform presentation 190. Důvěrné

64% improvement vs IFN β-1a 89% improvement vs IFN β-1a OPERA I and OPERA II Exploratory Endpoint: Proportion of Patients With NEDA OPERA I OPERA II 64% improvement vs IFN β-1a p<0.0001 89% improvement vs IFN β-1a p<0.0001 CZ/NEUR/0217/0008 NEDA is defined as: no protocol-defined relapses, no CDP events, no new or enlarging T2 lesions, and no Gd-enhancing T1 lesions ITT *Compared using the Cochran–Mantel–Haenszel test stratified by geographic region (US vs ROW) and baseline EDSS score (<4.0 vs ≥4.0). EDSS, Expanded Disability Status Scale; Gd+, gadolinium enhancing; IFN, interferon; ROW, rest of the world. Hauser SL, et al. ECTRIMS 2015; 7-10 October 2015, Barcelona, Spain. Platform presentation 190. Důvěrné

Exploratory endpoint: Change in brain volume compared with IFN β-1a Percentage Change in Brain Volume from Baseline to Week 96 Week OPERA I Percentage Change in Brain Volume from Baseline to Week 96 Week OPERA II t_neda_cmh_IT_092_0.2, t_neda_cmh_IT_093_0.1 23.5% reduction in rate of brain volume loss vs IFN β-1a p<0.0001 23.8% reduction in rate of brain volume loss vs IFN β-1a p=0.0001 CZ/NEUR/0217/0008 ITT Exploratory endpoint IFN, interferon. Hauser SL, et al. ECTRIMS 2015; 7-10 October 2015, Barcelona, Spain. Platform presentation 190. Důvěrné

ORATORIO Time to onset of 24-week CDP (secondary endpoint #1) P values based on log-rank test; Hazard ratio estimated by Cox regression. CDP, confirmed disability progression; CI, confidence interval.

Reakce související s infuzí (IRR) u poolované OPERA I a OPERA II podle dávky a závažnosti*, **, † Mírné Středně závažné Závažné Život ohrožující IFN β-1a 44 μg Ocrelizumab 600 mg Dávka 1 Dávka 2 Dávka 3 Dávka 4 Dávka 1 Dávka 2 Dávka 3 Dávka 4 CZ/NEUR/0217/0008 * Pool A **Čísla ve sloupcích reprezentují poměr pacientů se zkušeností s IRR †Klasifikace podle běžných terminologických kritérií (CTCAE): Stupeň 1 Mírné; asymptomatické nebo mírné symptomy; Stupeň 2 Středně závažné; indikována minimální, lokální nebo neinvazivní intervence; Stupeň 3 Závažné nebo medicínsky významné, ale nikoli okamžitě život ohrožující; Stupeň 4 Život ohrožující následky; indikována okamžitá intervence; Stupeň 5 Smrt v souvislosti s nežádoucími účinky. t_ae_irr_int_inf_all_spa 17AUG2015 15:32 Poznámka: všem bylo podáno 100 mg i.v. methylprednisolonu Důvěrné

Přehled infekcí a závažných infekcí Poolovaná OPERA I a II* (96týdenní kontrolované období) ORATORIO** IFN β-1a 44 μg N = 826 Ocrelizumab 600 mg N = 825 Placebo N = 239 Ocrelizumab 600 mg N = 486 Pacienti s infekcí, n (%) 433 (52,4) 482 (58,4) 162 (67,8) 339 (69,8) Nejběžnější typy infekcí, n (%) URTI 87 (10,5) Nazofaryngitida 84 (10,2) UTI 100 (12,1) - Bronchitida 29 (3,5) URTI 125 (15,2) Nazofaryngitida 122 (14,8) UTI 96 (11,6) Bronchitida 42 (5,1) URTI 14 (5,9) Nazofaryngitida 65 (27,2) UTI 54 (22,6) Chřipka 21 (8,8) Bronchitida 12 (5,0) URTI 53 (10,9) 110 (22,6) UTI 96 (19,8) Chřipka 56 (11,5) Bronchitida 30 (6,2) Pacienti se závažnými infekcemi, n (%) 24 (2,9) 11 (1,3) 14 (5,9) 30 (6,2) CZ/NEUR/0217/0008 **2:1 randomizace *Pool A Důvěrné 66

Četnost incidence malignit napříč studiemi Malignity (včetně non-melanomových kožních nádorů) IFN (RRS) or Placebo (PPRS) OCR Epidemiologie Všechny RRS+PPRS Četnost incidence / 100 pacient-roků 0,195 [0,053; 0,499] 0, 425 [0,256; 0,664] 0,48 [0,34, 0,65] 0,67 [0,63; 0,71] Dánsko (Nielsen 2006) Data z ramene s placebem 9 studií MS prováděných u pacientů mezi 18 a 55 lety (Analytica LA-SER 2015) Rakovina prsu INF (RRS) nebo placebo (PPRS) OCR Epidemiologie Všechny RRS + PPRS ženy Četnost incidence / 100 pacient-roků [0; 0,293] 0,261 [0,105; 0,538] 0,21 [0,18; 0,23] 0,14 [0,11; 0,16] 0,277 [0,270; 0,284] 0,13 [0,05; 0,28] Dánsko (Nielsen 2006) Kanada (Kingwell 2012) VB ženy 50–55 let (Cancer Výzkum VB, 2015) Data z ramene s placebem 9 studií MS prováděných u pacientek mezi 18 a 55 lety (Analytica LA-SER 2015) CZ/NEUR/0217/0008 Důvěrné

Daclizumab Protilátka proti CD25 – součást receptoru pro interleukin-2

Mode of action of daclizumab CONFIDENTIAL - DO NOT DISTRIBUTE Mode of action of daclizumab 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 high-affinity (βγ) receptor Activation CD4+ Tact cell CD56bright IL-2 intermediate-affinity (βγ) receptor Daclizumab IL-2 Adapted from: Amaravadi L, et al. Poster presentation at AAN 2015;P1.149; Zinbryta® (daclizumab) SmPC. February 2017.

CONFIDENTIAL - DO NOT DISTRIBUTE Effects of IL-2 pathway modulation include selective antagonism of activated T-cell responses and expansion of immunoregulatory CD56bright NK cells IL-2 high-affinity (βγ) receptor IL-2 intermediate-affinity (βγ) receptor Activation Daclizumab IL-2 CD4+ CD56bright CD56bright CD56bright CD4+ Tact cell CD56bright CD56bright CD4+ Tact cell CD56bright Adapted and elaborated from: Amaravadi L, et al. Poster presentation at AAN 2015;P1.149; Zinbryta® (daclizumab) SmPC. February 2017.

CONFIDENTIAL - DO NOT DISTRIBUTE Expansion of CD56bright NK cells may contribute to the balance between immunomodulatory and proinflammatory responses1–3 Immunoregulatory cells* Proinflammatory cells* CD4+ Tact cell CD4+ Tact cell CD4+ Tact cell CD4+ Tact cell CD56bright CD4+ Tact cell CD4+ Tact cell CD4+ Tact cell CD56bright CD4+ Tact cell CD56bright CD56bright CD4+ Tact cell CD4+ Tact cell CD4+ Tact cell CD4+ Tact cell CD56bright CD56bright CD56bright CD56bright CD56bright CD56bright CD8+ Tact cell CD8+ Tact cell CD8+ Tact cell CD8+ Tact cell Treg CD8+ Tact cell B cell Treg B cell Expansion of CD56bright NK cells Multiple sclerosis *Simplified schematic, not representative of all immunoregulatory and proinflammatory cells. Adapted from: 1. Wiendl H, Gross CC. Nat Rev Neurol. 2013;9:394–404; 2. Sospedra M, Martin R. Annu Rev Immunol. 2005;23:683–747; 3. Lin YC, et al. Ann Clin Transl Neurol. 2015;2:445–55.

Primární cíl: roční počet relapsů CONFIDENTIAL - DO NOT DISTRIBUTE Primární cíl: roční počet relapsů At Week 521,2 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 SELECT: vs placebo The 300 mg dose did not provide additional benefit over the licensed 150 mg dose Annualised relapse rate (95% CI) Up to Week 1442,3 IM IFN beta-1a (n=922) Daclizumab (n=919) 45% relative reduction P<0.0001 DECIDE: vs IFN beta-1a Annualised relapse rate (95% CI) CI, confidence interval. 1. Gold R, et al. Lancet. 2013;381:2167–75; 2. Zinbryta® (daclizumab) SmPC. February 2017; 3. Kappos L, et al. N Engl J Med. 2015;373:1418–28.

CONFIDENTIAL - DO NOT DISTRIBUTE DECIDE: MRI léze DECIDE: vs IFN beta-1a1,2 New or newly enlarging T2 lesions* Weeks 0–96 New Gd+ lesions† At Week 96 New T1 lesions† Weeks 0–96 75% relative odds reduction P<0.0001 54% relative reduction P<0.0001 52% relative reduction P<0.0001 n=841 n=864 n=909 n=900 n=908 n=899 IM IFN beta-1a Daclizumab Significant reductions in MRI lesions for daclizumab 150 mg versus IFN beta-1a observed at 24 weeks1 and maintained up to 144 weeks3 *Secondary endpoint. †Tertiary endpoint. MRI, magnetic resonance imaging. 1. Kappos L, et al. N Engl J Med. 2015;373:1418–28; 2. Zinbryta® (daclizumab) SmPC. February 2017; 3. Arnold D, et al. Poster presentation at ECTRIMS 2015;P556.

12-week confirmed disability progression CONFIDENTIAL - DO NOT DISTRIBUTE 12-week confirmed disability progression SELECT: vs placebo1,2 DECIDE: vs IFN beta-1a1,3 Up to Week 144† Time on study (weeks) 5 10 15 20 16% relative risk reduction HR: 0.84 (95% CI: 0.66–1.07) P=0.16 16% 20% 12 24 36 48 60 72 84 96 108 120 132 144 Up to Week 52* 6% 13% 57% relative risk reduction HR: 0.43 (95% 0.21–0.88) P=0.021 5 10 15 20 12 24 36 48 52 Patients with confirmed disability progression (%) Time on study (weeks) Daclizumab (n=201) Placebo (n=196) Patients with confirmed disability progression (%) No. at risk Placebo Daclizumab No. at risk IM IFN beta-1a Daclizumab 922 919 873 892 820 851 777 803 728 685 733 647 697 624 665 600 640 446 484 347 345 244 253 128 196 201 192 198 183 188 169 182 164 179 110 128 *Tertiary endpoint. †Secondary endpoint. HR, hazard ratio. 1. Zinbryta® (daclizumab) SmPC. February 2017; 2. Gold R, et al. Lancet. 2013;381:2167–75; 3. Kappos L, et al. N Engl J Med. 2015;373:1418–28.

24-week confirmed disability progression CONFIDENTIAL - DO NOT DISTRIBUTE 24-week confirmed disability progression SELECT: vs placebo1,2 DECIDE: vs IFN beta-1a1,3 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 13% 18% 20 10 25 15 5 Up to Week 144† Time on study (weeks) Up to Week 52* 25 Placebo (n=196) Daclizumab (n=201) 20 76% relative risk reduction HR: 0.24 (95% CI: 0.09–0.63) P=0.0037 15 Patients with confirmed disability progression (%) Patients with confirmed disability progression (%) 11% 10 5 2.6% 12 24 36 48 52 Time on study (weeks) No. at risk 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 No. at risk 196 201 192 198 183 190 171 185 167 184 114 132 *Post-hoc analysis. †Tertiary endpoint. 1. Zinbryta® (daclizumab) SmPC. February 2017; 2. Biogen, data on file; 3. Kappos L, et al. N Engl J Med. 2015;373:1418–28.

SELECT: Patients achieving NEDA CONFIDENTIAL - DO NOT DISTRIBUTE SELECT: Patients achieving NEDA SELECT: vs placebo Placebo (n=196) Daclizumab (n=201) Patients with NEDA (%) OR: 6.31 (95% CI: 3.59–11.11) P<0.0001 Week 52 POZOR! Roční studie! OR, odds ratio. Havrdová E, et al. Mult Scler. 2014;20:464–70.

DECIDE: Patients achieving NEDA CONFIDENTIAL - DO NOT DISTRIBUTE DECIDE: vs IFN beta-1a 12 24 36 48 60 72 84 96–144 EDSS MRI          Overall: OR: 2.06 (95% CI: 1.59–2.66) P<0.0001 OR: 1.51 (95% CI: 1.23–1.84) P<0.0001 OR: 2.96 (95% CI: 2.36–3.71) P<0.0001 IM IFN beta-1a Daclizumab Patients achieving NEDA (%) n=118 / 833 n=200 / 813 n=282 / 864 n=367 / 884 n=173 / 773 n=347 / 776 *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 versus 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. Kappos L, et al. Mult Scler. 2016; 1352458516683266 [Epub ahead of print].

CONFIDENTIAL - DO NOT DISTRIBUTE SELECTED 3-year interim analysis: Annualised whole brain volume change1 Placebo Year 1 From first dose of daclizumab Year 1 Year 2 Year 3 −0.32 (−0.34) −0.57 (−0.50) Mean (median) annualised change in whole brain volume (%) −0.77 (−0.63) −0.74 n= 194 383 362 293 Average brain volume change in healthy controls reported as 0.27% ± 0.15% per year (−0.20% ± 0.13% in subjects aged <35 years, −0.32% ± 0.14% in subjects >35 years)2 Secondary endpoint in SELECTED. Adapted from: 1. Gold R, et al. BMC Neurol. 2016;16:117; 2. De Stefano N, et al. J Neurol Neurosurg Psychiatry. 2016;87:93–9.

DECIDE: Annualised whole brain volume change CONFIDENTIAL - DO NOT DISTRIBUTE DECIDE: Annualised whole brain volume change Weeks 0–24 Weeks 24–96 Weeks 96–144 IM IFN beta-1a (n=907) Daclizumab (n=899) IM IFN beta-1a (n=907) Daclizumab (n=899) IM IFN beta-1a (n=149) Daclizumab (n=161) −0.745 (−6.52 to 3.65) −0.674 (−6.78 to 5.42) −0.549 (−3.88 to 1.02) −0.511 (−3.61 to 0.77) −0.377 (−2.17 to 1.21) −0.379 (−2.02 to 1.08) Median (range) annualised change in brain volume (%) Median (range) annualised change in brain volume (%) Median (range) annualised change in brain volume (%) P<0.001 P=0.033 Overall from baseline to Week 96 the PBVC was significantly lower for patients receiving daclizumab: daclizumab: −0.553 (n=907) versus IM IFN beta-1a: −0.580 (n=899); P<0.001 PBVC, percentage brain volume change Kappos L, et al. N Engl J Med. 2015;373:1418–28; Arnold DL, et al. ECTRIMS 2015;P558; Biogen data on file.

Nežádoucí účinky hepatální kožní lymfadenopatie většinou důsledek zvýšené přítomnosti NK buněk

CONFIDENTIAL - DO NOT DISTRIBUTE Lehké kožní příznaky Pompholyx eczema Krueger JG, et al. Adv Ther. 2016;33:1231–45.

Středně těžké kožní příznaky CONFIDENTIAL - DO NOT DISTRIBUTE Středně těžké kožní příznaky Eczema lesions Krueger JG, et al. Adv Ther. 2016;33:1231–45.

CONFIDENTIAL - DO NOT DISTRIBUTE Těžké kožní příznaky Small to large areas of erythema (macules and patches of erythema) and some dermatographism caused by scratching-delayed-type hypersensitivity reaction Krueger JG, et al. Adv Ther. 2016;33:1231–45.

Cladribine Under review Purine nucleoside analogue Reduces circulating T and B lymphocytes Interferes with DNA synthesis and repair through incorporation into DNA and through inhibition of enzymes involved in DNA metabolism Oral administration Under review

July 2006 CLARITY: Significant reduction in annualised relapse rate vs placebo over 2 years (primary endpoint) Additional notes The annualized relapse rate (ARR) for patients treated with cladribine tablets was 0.14 (3.5 mg/kg) and 0.15 (5.25 mg/kg), compared to an ARR of 0.33 for placebo This corresponds to relative reductions of 58% (3.5 mg/kg) and 55% (5.25 mg/kg), and these results were highly statistically significant with p-values of <0.001 A qualifying relapse was defined as a 2-grade increase in ≥1 Kurtzke Functional System (KFS) or a 1-grade increase in ≥2 KFS, excluding changes in bowel/bladder or cognition, in the absence of fever, lasting for ≥24 hours, and preceded by ≥30 days of clinical stability or improvement p-values are based on Wald Chi-square test from analysis of number of qualifying relapses using a Poisson regression model with fixed effects for treatment group and region and with log of time on study as an offset variable Relative reductions are calculated as the ratio of difference in ARR relative to that in the placebo group, for qualifying relapses CI, confidence interval; RR, relative reduction. Intent-to-treat population. Giovannoni G et al. N Engl J Med 2010;362:416–26. © Merck KGaA Darmstadt/Germany 85

CLARITY: Significant increase in proportion of patients with NEDA-3 July 2006 CLARITY: Significant increase in proportion of patients with NEDA-3 Additional notes Odds ratios (ORs) are for each cladribine tablets group vs placebo, and are estimated using a logistic regression model with fixed effects for treatment group and region p-values are for each cladribine tablets group vs placebo and are based on a Wald Chi-squared test from a logistic regression model with fixed effects for treatment group and region Significantly greater proportions of patients with disease-free endpoints vs placebo at 2 years, including: Relapse free: cladribine 3.5 mg/kg vs placebo: OR 2.69, 95% CI: 1.96, 3.68, p<0.0001; cladribine 5.25 mg/kg vs placebo: OR 2.59, 95% CI : 1.90, 3.53, p<0.0001 Progression free: cladribine 3.5 mg/kg vs placebo: OR 1.87 95% CI: 1.19, 2.94, p=0.0064; cladribine 5.25 mg/kg vs placebo: OR 1.33, 95% CI: 0.88, 2.02, p=0.1747 MRI lesion free: cladribine 3.5 mg/kg vs placebo: OR 5.52, 95% CI: 3.68, 8.27, p<0.0001; cladribine 5.25 mg/kg vs placebo: OR 6.87, 95% CI: 4.63, 10.21, p<0.0001 aProgression free was defined as having no 6-month sustained change in EDSS score. bMRI lesion activity free was defined as having no new T1 Gd+ lesions and no active T2 lesions on cranial MRI. cNEDA-3 was defined as having no relapses, no 6-month sustained change in EDSS score, no new T1 Gd+ lesions and no active T2 lesions. Post hoc analysis. EDSS, Expanded Disability Status Scale; Gd+, gadolinium-enhancing; MRI, magnetic resonance imaging; NEDA, no evidence of disease activity; NS, not significant. Giovannoni G et al. Lancet Neurol 2011;10:329–37. © Merck KGaA Darmstadt/Germany 86

Cytostatika: CPA (1993), mitoxantron (1996) dnes omezeno na případy, kdy není indikována eskalační léčba začátek chronické progrese srovnatelný efekt možno použít jako indukční léčbu před zahájením DMD terapie

Léčba sekundární progrese neexistuje mezinárodní konsensus Siponimod (další modulátor S1P) – mírný klinický efekt  opakované pulsy methylprednisolonu  pulsní léčba MP a CPA (Harvardské schéma)  pulsní léčba MP a mitoxantronem 20mg (Edanovo schéma) půl roku nebo mitoxantron v nižší dávce déle a 3 měsíce (Evropská multicentrická studie - Hartung) Farmakovigilance: používán v EU minimálně!, AEs musí být diskutovány s pacientem ve světle krátké možnosti použití a efektu, který není trvalý echo – před každou infusí, sledování 5 let TRAL 1:333 případů  dispenzarizace

Léčba primární progrese méně známek zánětu na MRI i v CSF, méně aktivovaných lymfocytů i tvorby IgG, více destruovaných ODC i axonů někdy je úspěšné užít stejné metody jako u sekundární progrese klinické studie Fingolimod – negativní Ocrelizumab – pozitivní, v reg. řízení

Léčba maligního průběhu nemoci stále experimentální terapie (> 700 pac.) u pacientů, kteří selhali na alespoň 1 terapii 1. linie a 1 terapii 2. linie u pacientů, kde hrozí ztráta chůze, ale EDSS nepřesahuje 5,5 u pacientů, kde je dokumentovaná aktivita choroby u pacientů v prvních letech nemoci lze očekávat určitý efekt z imunoablace doplněné HSCT efekt je protizánětlivý!, ne neuroreparativní Studie nemají konzistentní inclusion criteria ani režimy imunoablace !