DAI TRIAL ALLA PRATICA CLINICA: NOVITÀ NELLA TERAPIA DELLA SCLEROSI MULTIPLA. Diego Centonze

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1 DAI TRIAL ALLA PRATICA CLINICA: NOVITÀ NELLA TERAPIA DELLA SCLEROSI MULTIPLA Diego Centonze

2 Disability Due finestre di opportunità terapeutica Window 1 Window 2 Optimise early Breakthrough disease not managed Delayed optimisation Treat early Disease onset Monitor Early treatment optimisation Time Adapted from: Ziemssen T, et al. J Neurol. 2016;263: ; Tintoré M, et al. Brain. 2015;138:

3 Razionale per il trattamento precoce della SM Comi et al Lancet 2016

4 EDSS 3: maggiore risposta al trattamento Adattata da Comi G et. Clin Ther 2009.

5 DSS Fase 2: La progressione è indipendente dalla durata della fase 1 La SM è una patologia a due fasi Fase 1: La progressione dipende dall infiammazione Anni dall insorgenza clinica SM Leray et al., Brain 2010

6 DMTs attualmente disponibili in Italia Mild to moderate disease Dimethyl fumarate (oral) Peginterferon beta IFN beta (IM/SC) Glatiramer acetate (SC) Teriflunomide (oral) Rapidly evolving severe disease Breakthrough disease More active disease Natalizumab (IV) Fingolimod (oral) Alemtuzumab (IV) Daclizumab (SC) Refractory disease Safety issues Rescue or experimental therapies Natalizumab (IV) Fingolimod (oral) Alemtuzumab (IV) Daclizumab (SC) Refractory disease Safety issues Adapted from: Sölberg Sørensen P. Curr Opin Neurol. 2014;27: Confidential- not to be disseminated, copied and modified.

7 Efficacia verso placebo Riduzione ARR verso placebo * Studi di fase ** 80% 70% 68% 60% 50% 54% 54% 49% 40% 30% 36% 34% 32% 32% 36% 31% 29% 20% 10% 0% * Risultati a 2 anni di trattamento tranne che per peginterferon e daclizumab (1 anno) ** Risultati tratti dagli studi di fase verso placebo. I risultati di studi clinici indipendenti non possono essere paragonati direttamente. Grafico elaborato da: AFFIRM: Polman CH et al. N Engl J Med 2006; FREEDOMS: Kappos L et al. N Engl J Med 2010; ANALISI POOLED DEFINE e CONFIRM: Viglietta et al. Clinical and Transational Neurology 2015; IFNβ MS Study Group, Neurology 1993; MSCRG: Jacobs et al. Ann Neurol 1996; PRISMS Study Group Lancet 1998; TOWER:Confavreux et al Lancet Neurol. 2014; TEMSO: O Connor et al, New England J. Med 2011; Johnson et al. Neurology 1995; SELECT: Gold et al. Lancet 2013

8 Efficacia verso placebo Riduzione progressione di disabilità a 12 settimane verso placebo * Studi di fase ** 60% 57% 50% 40% 42% 38% 30% 30% 32% 30% 31,5% 30% 24% 20% 10% 12% NS 0% Natalizumab (AFFIRM) Daclizumab (SELECT)* Fingolimod (FREEDOMS) DMF BID (pooled) Peginterferon Q2W (ADVANCE)* Teriflunomide Teriflunomide 14 mg 14 mg (TEMSO) (TOWER) IFN beta 1 a SC- 44 (PRISM) IFN beta 1b SC (MS study Group) Glatiramer acetato (Johnson) * Risultati a 2 anni di trattamento tranne che per peginterferon e daclizumab (1 anno) ** Risultati tratti dagli studi di fase verso placebo. I risultati di studi clinici indipendenti non possono essere paragonati direttamente. Grafico elaborato da: AFFIRM: Polman CH et al. N Engl J Med 2006; FREEDOMS: Kappos L et al. N Engl J Med 2010; ANALISI POOLED DEFINE e CONFIRM: Viglietta et al. Clinical and Transational Neurology 2015; IFNβ MS Study Group, Neurology 1993; MSCRG: Jacobs et al. Ann Neurol 1996; PRISMS Study Group Lancet 1998; TOWER:Confavreux et al Lancet Neurol. 2014; TEMSO: O Connor et al, New England J. Med 2011; Johnson et al. Neurology 1995; SELECT: Gold et al. Lancet 2013

9 Efficacia verso placebo Riduzione numero lesioni Gd+ verso placebo * Studi di fase ** 100% 90% 80% 92% 83% 86% 79% 82% 80% 70% 60% 50% 52% 40% 30% 20% Riduzione numero lesioni in T2 verso placebo * Studi di fase ** 10% 0% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 83% 78% Natalizumab (AFFIRM) DMF BID (pooled) 70% Daclizumab (SELECT) 74% Fingolimod (FREEDOMS) 67% Peginterferon Q2W (ADVANCE)* * Risultati a 2 anni di trattamento tranne che per peginterferon e daclizumab (1 anno) ** Risultati tratti dagli studi di fase verso placebo. I risultati di studi clinici indipendenti non possono essere paragonati direttamente. Grafico elaborato da: AFFIRM: Polman CH et al. N Engl J Med 2006; FREEDOMS: Kappos L et al. N Engl J Med 2010; ANALISI POOLED DEFINE e CONFIRM: Viglietta et al. Clinical and Transational Neurology 2015; IFNβ MS Study Group, Neurology 1993; MSCRG: Jacobs et al. Ann Neurol 1996; PRISMS Study Group Lancet 1998; TOWER:Confavreux et al Lancet Neurol. 2014; TEMSO: O Connor et al, New England J. Med 2011; Johnson et al. Neurology 1995; SELECT: Gold et al. Lancet 2013

10 Hauser SL; Ann Neurol 2013

11 Evoluzione degli obiettivi della terapia della SM Gestione dei sintomi Rallentamento della progressione di disabilità Miglioramento funzionale NEDA 3 EDSS 1 MSFC 2 Miglioramento sostenuto della disabilità IFNβ-1b IFNβ-1a SC IFNβ-1a IM GA Mitoxantrone Natalizumab 2014 Teriflunomide 2016 Fingolimod Daclizumab Dimetil Fumarato PEG-IFNβ1a SC Le date si riferiscono all approvazione dei singoli farmaci nell Unione Europea. Alemtuzumab 1 Kurtzke J et al. Neurology 1983; 2 Whitaker J et al. Mult Scler 1995; 3 Havrdova E et al. Lancet Neurol 2009; 4 Phillips J et al. Mult Scler 2011.

12 No evidence of disease activity No relapses No evidence of clinical disease No CDP NEDA No T1 Gd + lesions No evidence of MRI disease No new / enlarging T2 lesions

13 Relevance of 2 years NEDA to predict long-term disease control RESULTED IN 78.3 % POSITIVE PREDICTIVE VALUE FOR DISEASE-FREE STATUS* NO DISABILITY PROGRESSION AT 2 YEARS AT 7 YEARS 1 Adapted from Hardova E, et al. Lancet Neurol 2009;8: ; Rotstein DL, et al. JAMA Neurol 2015;72(2):

14 Predictors of NEDA in early RRMS pts At 1-yr FU: 54% of pts had NEDA Nygaard GO et al. Plos One 2015;10:e Only predictor of NEDA: 2 nd line Tx (fingolimod or natalizumab) 58% vs 10% NEDA in 2 nd line vs 1 st line Tx Tx assignment seems to be the only predictor of NEDA. NEDA pts seem to regress in EDSS

15 Rotstein DL; JAMA Neurol 2015

16 OUTLINE: 1. Natalizumab 2. Fingolimod 3. Alemtuzumab 4. Daclizumab 5. Ocrelizumab 6. Cladribine

17 OUTLINE: 1. Natalizumab 2. Fingolimod 3. Alemtuzumab 4. Daclizumab 5. Ocrelizumab 6. Cladribine

18 Natalizumab riduce la gravita delle ricadute rispetto al placebo % Pazienti con aumento EDSS 1 in seguito a ricaduta Nel totale popolazione esaminata e nei pazienti con EDSS basale <3, natalizumab riduce significativamente la gravità delle ricadute rispetto al placebo. Lublin F.D. et al., Multiple Sclerosis and Related Disorders, 2014

19 Natalizumab è l unica terapia approvata di 2 linea con risultati sulla riduzione della disabilità residua post ricaduta Variazione media EDSS pre-post relapse* 1,0 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0,0 *P= ,39 0,30 0,31 0,06 n=144 n=140 n=196 n=116 AFFIRM FREEDOMS Placebo Natalizumab Fingolimod 0.5 mg *I dati ottenuti in studi indipendenti non sono direttamente confrontabili. Cutter G. et al, AAN 2013 Lublin F.D. et al., Multiple Sclerosis and Related Disorders2014

20 Natalizumab riduce la comparsa di nuove lesioni Gd+ e la loro evoluzione in black holes N. Medio di nuove lesioni Gd+ (1-6 mesi) % Pazienti con nuove lesioni Gd+ (1-6 mesi) che evolvono in lesioni ipointense in T1 a 12 mesi 9,6 68% -93% # -88% # - 62% 26% 0,7 1,1 N=71 N=68 N=74 N=40 N=38 Elaborato da Miller DH et al. N Engl J Med 2003; Dalton CM et al. J Neurol *Dati combinati natalizumab 3 mg/kg + natalizumab 6 mg/kg. #p<0,001. p<0,01.

21 Valutazione del rischio RISCHIO SM RISCHIO PML EFFICACIA TYSABRI Rischio di progressione della disabilità (6 anni di follow-up 318 pz - raggiungimento EDSS 4 per pz con EDSS <3; raggiungimento EDSS 6 per pz con EDSS >3) Tutti EDSS < 3.0 EDSS 3.0 Pazienti che sospendono Tysabri 1 su 3 (da 2 a 4) 1 su 5 (da 3 a 9) 1 su 2 (da 2 a 3) Pazienti che proseguono Tysabri 1 su 12 (da 8 a 21) 1 su 20 (da 11 a 90) 1 su 7 (da 5 a 15) Modificato da Prosperini et al., MSJ 2015 Rischio di PML Index 1-24 mesi mesi mesi JCV- NA NA 1 su su su su Da 1 su a 1 su su a 1 su JCV+ IS- 0,9-1,5 >1.5 Da 1 su a 1 su Da 1 su a 1 su Da 1 su a 1 su 500 Da 1 su 333 a 1 su 143 Da 1 su 500 a 1 su 333 Da 1 su 125 a 1 su 100 IS+ NA Da 1 su a 1 su Da 1 su 250 a 1 su 125 Da 1 su 167 a 1 su 125 Modificata da Linee Guida Tysabri versione 16

22 OUTLINE: 1. Natalizumab 2. Fingolimod 3. Alemtuzumab 4. Daclizumab 5. Ocrelizumab 6. Cladribine

23 Fingolimod riduce rapidamente ARR e progressione della disabilità che si mantengono stabili nel lungo periodo Popolazioni aggregate FREEDOMS + TRANSFORMS a 84 mesi) ARR a 84 mesi EDSS a 84 mesi LONGTERMS is an open-label, single-arm, long-term follow-up extension study of Phase II, III and IIIb trials, monitoring the long-term safety, tolerability and effectiveness of fingolimod. Data for patients receiving fingolimod 0.5 mg from LONGTERMS. TRANSFORMS n = 732; pooled FREEDOMS, n = 982. ARR = annualised relapse rate; EDSS = Expanded Disability Status Scale. Cohen JA, et al. Poster presented at: AAN 2016; Vancouver.

24 Fingolimod reduces serum NfL levels in RRMS patients Treatment with fingolimod led to an early and sustained significant reduction of NfL versus INF beta-1a and versus placebo Kuhle J et al. Poster presented at AAN 2017

25 Incidenza di PML nel trattamento con fingolimod (dato aggiornato al 31 maggio 2017) Ad oggi si sono verificate 13 PML in pazienti in trattamento con fingolimod senza precedente esposizione a natalizumab. Si tratta di 13 casi su > pazienti 0,061 (0,032; 0,104)/1000 pazienti L incidenza si mantiene al di sotto di 1 caso/ pazienti Esposizione mondiale cumulativa negli studi clinici e nel post marketing. Aggiornamento al Novartis Pharmaceutical Q Financial Report (Maggio 2017)

26 OUTLINE: 1. Natalizumab 2. Fingolimod 3. Alemtuzumab 4. Daclizumab 5. Ocrelizumab 6. Cladribine

27 Alemtuzumab CARE MS II Durable efficacy in the absence of continous MS therapy Objective: efficacy and safety of alemtuzumab in treatment-naive patients with active relapsing-remitting MS (RRMS) (CARE-MS I). Core Study Extension Study Year 1 Year 2 Year 3 Year 4 Year 5 Month: Randomized 2:1 (Alemtuzumab: SC-IFNB-1a) Alemtuzumab 12 mg IV Course 1 Course 2 5 consecutive 3 consecutive doses doses As needed retreatment or other DMT Retreatment criteria: 1 protocol-defined relapse, or 2 new/enlarging T 2 hyperintense and/or new Gdenhancing T 1 brain or spinal lesions on MRI Classification of evidence: This study provides Class III evidence that alemtuzumab durably improves efficacy outcomes and slows BVL in patients with RRMS. Neurology 2017;89:1 10 E. Havrdova et al, Neurology 89, September 12,2017

28 Results Of the 367 alemtuzumab-treated patients who completed CARE MS II, 349 (95,1%) continued in the extension study and respectively: 239 (68,5%) received just 2 courses of alemtuzumab, 341 (97.7%) received no other DMT 235 (67.3%) received neither alemtuzumab retreatment nor other DMT 335 (96%) remained on study throught Month 60. Re-treatments Of the 110 patients who received alemtuzumab retreatment, respectively 77 (70.0%) received another 1 re-treatment courses 28 (25.5%) received other 2 re-treatments courses 5 (4.5%) received 3 alemtuzumab re-treatment courses E. Havrdova et al, Neurology 89, September 12,2017

29 Efficacy Results Relapse was the most common reason for alemtuzumab re-treatment (51.0% of re-treatment courses for which a reason was provided); 25,9% of re-treatments were prompted by MRI lesion activity 23,1% by combined relapse and MRI lesion activity E. Havrdova et al, Neurology 89, September 12,2017

30 CDI Confirmed Desease Improvement 33,4% of pts. achieved 6-month confirmed disability improvement (CDI). E. Havrdova et al, Neurology 89, September 12,2017

31 OUTLINE: 1. Natalizumab 2. Fingolimod 3. Alemtuzumab 4. Daclizumab 5. Ocrelizumab 6. Cladribine

32 Adjusted ARR (95% CI) SELECT Riduzione ARR 0,6 0,5 0,4 0,3 Adjusted ARR at end of trial (week 52) 54% relative reduction vs placebo P<0.0001* 50% relative reduction vs placebo P=0.0002* 0,2 0,46 0,1 0,21 0,23 0 Placebo (n=196) DAC HYP 150 mg (n=201) DAC HYP 300 mg (n=203) Elaborato da Gold R, et al; SELECT study investigators. Lancet. 2013

33 Patients with 6-month confirmed disability progression SELECT Riduzione progressione di disabilità a 24 settimane 12% 10% 8% 6% 56% relative reduction vs placebo 95% CI, 16-77% P= % 10% 2% 4% 0% Placebo (n=196) DAC HYP Pooled* (n=404) *DAC HYP Pooled includes both the 150 mg and 300 mg dosing groups Elaborato da Havrdova E, et al. ECTRIMS 2012:P949.

34 SELECT % pazienti NEDA** 36% 41% 39% P<0.0001* P<0.0001* P<0.0001* 11% Placebo (n=196) DAC HYP 150 mg (n=201) DAC HYP 300 mg (n=203) DAC HYP combined (n=404) * verso placebo ** NEDA= No Evidence of Disease Activity Elaborato da Havrdova E, et al; Mult. Scler. J

35 OUTLINE: 1. Natalizumab 2. Fingolimod 3. Alemtuzumab 4. Daclizumab 5. Ocrelizumab 6. Cladribine

36 Growing Evidence Supports Multiple Roles for B Cells in MS Pathophysiology 1. Autoantibody production Increased tissue damage through complement activation or ADCC 4. Ectopic (or tertiary) follicle-like structures Lymphogenesis 2. Antigen presentation Activation of T cells and signals to promote T-cell activity IL-10 TNF-α LT-α IL-6 ADCC = antibody-dependent cellmediated cytotoxicity. 3. Cytokine production Activation of other immune cells

37 1:1 Randomisation OLE screening period OLE OPERA I and II: Two identical studies evaluating the efficacy and safety of ocrelizumab in RMS RMS diagnosis yrs 2 clinical relapses within last 2 yrs or 1 relapse in last yr EDSS of Safety follow-up 48 weeks from date of last infusion B-cell monitoring

38 Adjusted ARR at 96 Weeks* Adjusted ARR at 96 Weeks* Primary endpoint: Significant reduction in ARR compared with IFN β- 1a OPERA I OPERA II 0,5 0,5 0,4 0,3 0,292 46% ARR reduction vs IFN β-1a p< ,4 0,3 0,290 47% ARR reduction vs IFN β-1a p< ,2 0,156 0,2 0,155 0,1 0,1 0,0 IFN β-1a 44 μg (n=411) Ocrelizumab 600 mg (n=410) 0,0 IFN β-1a 44 μg (n=418) Ocrelizumab 600 mg (n=417)

39 Secondary endpoints: Significant reduction in CDP in the pre-specified pooled analysis of OPERA I and OPERA II Time to 12-week CDP Time to 24-week CDP Risk reduction: 40% HR (95% CI): 0.60 (0.45, 0.81); p= Risk reduction: 40% HR (95% CI): 0.60 (0.43, 0.84); p= n IFN β-1a OCR n IFN β-1a OCR

40 Secondary endpoint: Significant reduction in number of T1 Gd + lesions compared with IFN β-1a Mean Number of T1 Gd-enhancing Lesions per MRI Scan* Mean Number of T1 Gd-enhancing Lesions per MRI Scan* OPERA I OPERA II 0,5 0,5 0,416 0,4 0,4 0,3 0,2 0,286 94% Reduction vs IFN β-1a p< ,3 0,2 95% Reduction vs IFN β-1a p< ,1 0,1 0,0 IFN β-1a 44 μg (n=411) 0,016 Ocrelizumab 600 mg (n=410) 0,0 IFN β-1a 44 μg (n=418) 0,021 Ocrelizumab 600 mg (n=417)

41 ORATORIO: Phase III Study in primary progressive MS (PPMS) Study Design 1 Diagnosis of PPMS (2005 revised McDonald criteria)2 Age years EDSS CSF: elevated IgG index or >1 oligoclonal bands No history of RRMS, SPMS, or PRMS No treatment with other MS DMTs at screening 2:1 Randomisation # *Patients received methylprednisolone prior to each ocrelizumab infusion or placebo infusion. The blinded treatment period may be extended until database lock. #2:1 randomisation stratified by age ( 45 vs >45) and region (US vs ROW). Continued monitoring occurs if B cells are not repleted. BL, baseline; CSF, cerebrospinal fluid; DMT, disease-modifying therapy; EDSS, Expanded Disability Status Scale; i.v., intravenous; MRI, magnetic resonance imaging. 1. Montalban X, et al. Presented at the 31 st Congress of the European

42 ORATORIO: Study objectives and endpoints Objectives To evaluate the efficacy and safety of ocrelizumab compared with placebo in patients with PPMS Primary endpoint 12-week confirmed disability progression (CDP) Key secondary endpoints 24-week CDP Timed 25-foot walk (baseline to Week 120) T2 lesion volume (baseline to Week 120) Whole brain volume (Week 24 to Week 120) Adapted from Montalban X. et al. Presented at the American Academy of Neurology th Annual Meeting

43 Primary endpoint: Significant reduction in 12-week CDP Time to 12-week Confirmed Disability Progression 24% reduction in risk of CDP HR (95% CI): 0.76 (0.59, 0.98); p= Analysis based on ITT population; p- n 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. CDP, confirmed disability progression; Placebo Ocrelizumab

44 % Change from Baseline Walking Time (Mean, 95% CI) Secondary endpoint: Significant reduction in the progression rate of walking time Percent Change in Timed 25-Foot Walk From Baseline to Week % reduction vs placebo p=0.0404* *Analysis based on ITT population; p- value based non ranked ANCOVA at 120- week visit adjusted for baseline timed 25-foot walk, geographic region and age with missing values imputed by LOCF. Point estimates and 95% CIs based on MMRM analysis on logtransformed data adjusted for baseline timed 25-foot walk, geographic region and age. Placebo Ocrelizumab

45 Secondary endpoint: Significant reduction in the rate of whole brain volume loss Percent Change of Whole Brain Volume from Week 24 to Week % reduction vs placebo p=0.0206* -0.90% -1.1% n Placebo *Analysis based on ITT population with week 24 and at least one post-week 24 assessment; p-value based on MMRM at 120 week visit adjusted for week 24 brain volume, geographic region and age. CI, confidence interval; ITT, intent to treat. Ocrelizumab

46 OUTLINE: 1. Natalizumab 2. Fingolimod 3. Alemtuzumab 4. Daclizumab 5. Ocrelizumab 6. Cladribine

47 How does cladribine selectively deplete lymphocytes, with less effect on other immune cells? CLADRIBINE ❶ ❷ Cladribine accumulates intracellularly due to ADA resistance Cladribine enters cell via nucleoside transporter ❸ Cladribine is activated by specific kinases ❹ Activated cladribine induces lymphocyte reduction Activated cladribine is inactivated by a specific phosphatase *One of the kinases is deoxycitidine kinase (dck); the phosphatase is 5 -nucleotidase. ADA, adenosine deaminase Leist TP, Weissert R. Clin Neuropharmacol 2011;34:

48 Cladribine selectivity for B and T lymphocytes and the dck/5 NTase ratio CD4 + T lymphocytes CD8 + T lymphocytes Skin Heart Brain Ovary Liver Kidney Lung Testis germ cell Testis mrna expression of inactivating phosphatase a CD4 + T cells CD8 + T cells CD19 + B cells NK cells Monocytes mrna expression of activating kinase a mrna expression of inactivating phosphatase a mrna expression of activating kinase a 5 NTase, 5 -nucleotidase; dck, deoxycytidine kinase; mrna, messenger ribonucleic acid; NK, natural killer. Carson DA et al. Proc Natl Acad Sci U S A 1980;77:6865 9; Lotfi K et al. Leuk Lymphoma 2003;44: ; Carson DA et al. Blood 1983;62:737 43; Salvat C et al. AAN 2009 [P09.105]. Figure (left) adapted from Leist TP, Weissert R. Clin Neuropharmacol 2011;34:28 35 and (right) Salvat C et al. AAN 2009 [P09.105] 48

49 ARR (95% CI) a CLARITY: ARR a at 96 weeks (primary endpoint) p< p< ,33 (0.29, 0.38) ,14 (0.12, 0.17) 0,15 (0.12, 0.17) 0 Placebo (n=437) Cladribine Tablets 3.5 mg/kg (n=433) Cladribine Tablets 5.25 mg/kg (n=456) a A relapse was defined as an increase of 2 points in at least one functional system of the EDSS or an increase of 1 point in at least two functional systems (excluding changes in bowel or bladder function or cognition) in the absence of fever, lasting for at least 24 hours and to have been preceded by at least 30 days of clinical stability or improvement. Intent-to-treat population. ARR, annualized relapse rate; CI, confidence interval; RRMS, relapsing remitting MS Giovannoni G et al. N Engl J Med 2010;362:

50 Mean number of lesions/patient/scan least squares mean (SE) CLARITY: MRI lesions at 96 weeks (secondary endpoint) Placebo Cladribine Tablets 3.5 mg/kg Cladribine Tablets 5.25 mg/kg ,43 1,72 (0.08) 1.2 (0.06) , ) p<0.001 p<0.001 p< p<0.001 p< ,12 0,11 (0.05) (0.05) T1 Gd+ lesions 0,38 (0.07) p< ,33 (0.06) Active (new or enlarging) T2 lesions 0,43 (0.08) CU lesions 0,38 (0.08) Intent-to-treat population. Placebo, n=437; Cladribine Tablets 3.5 mg/kg, n=433; Cladribine Tablets 5.25 mg/kg, n=456 CU, combined unique; Gd+, gadolinium-enhancing; MRI, magnetic resonance imaging; RR, relative reduction; SE, standard error Giovannoni G et al. N Engl J Med 2010;362:416 26; Comi G et al. J Neurol 2013;260:

51 Patients surviving free from progression (%) CLARITY: post hoc subgroup analysis risk of 6- month confirmed EDSS progression over 2 years Placebo (n=437) Cladribine Tablets 3.5 mg/kg (n=433) HR vs placebo: % CI 0.36, 0.79, p= Baseline Time since study entry (months) This analysis did not censor patients who used rescue therapy before the 3- or 6-month confirmatory visit; 1 this analysis, therefore, recorded more total EDSS progressions than the original analysis in the CLARITY study 2 CI, confidence interval; EDSS, Expanded Disability Status Scale; HR, hazard ratio 1. Cook S et al. AAN 2016 [P3.058]; 2. Giovannoni G et al. N Engl J Med 2010;362:

52 Cladribine Tablets: proportion of patients free of disease activity over 2 years Relapses 80% relapse free Active T2 62% lesion free NEDA 47% T1 Gd+ 87% lesion free 6-month confirmed EDSS 91% progression free NEDA was defined as no relapses, no 6-month confirmed EDSS progression and no new T1 Gd+ lesions and no active T2 lesions on cranial MRI. Post hoc analysis Giovannoni G et al. Lancet Neurol 2011;10:

53 Conclusioni Un importante evoluzione del trattamento dell SM è data dall inizio precoce della terapia con immunomodulanti. Il Multiple Sclerosis Therapy Consensus Group raccomanda di inziare precocemente il trattamento con l obiettivo di spegnere l infiammazione e di ridurre il danno assonale. Nuovi outcomes di risposta Il trattamento precoce con un trattamento efficace e un elevato standard per la definizione di successo terapeutico possono significativamente migliorare gli outcomes della SM nel lungo termine Efficacia del trattamento Trattamento precoce Fox et al. Curr Opin. Neurol. 2012