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MS Academia: Multiple Sclerosis Advanced Course

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MS Academia: Multiple Sclerosis Advanced Course 13 September 2016 - London, UK MS Academia: Multiple sclerosis advanced course IMPROVING THE PATIENT’S LIFE THROUGH MEDICAL EDUCATION www.excemed.org Mark S. Freedman, HBSc, MSc, MD, CSPQ, FANA, FAAN, FRCPC Multiple Sclerosis Research Unit The Ottawa Hospital Ottawa, Canada Disclosure Declared the receipt of honoraria or consultation fees from: Actelion, BayerHealthcare, BiogenIdec, Chugai, EMD Canada, Genzyme, Merck Serono, Novartis, Hoffman La-Roche, Sanofi- Aventis, Teva Canada Innovation. He declared to be member of a company advisory board, board of directors or other similar group: Actelion, BayerHealthcare, BiogenIdec, Hoffman La-Roche, Merck Serono, Novartis, Opexa, Sanofi-Aventis and the participation in a company sponsored speaker’s bureau:Genzyme. Mark S. Freedman Efficacy and safety of immunomodulators in RR MS IMPROVING THE PATIENT’S LIFE THROUGH MEDICAL EDUCATION www.excemed.org Existing & Emerging MS therapies Other Phase I Lymphocyte CS-0777 BIIB033 trafficking Phase II Idebenone Phase III Firategrast Interferons ONO-4641 ELND-002 Marketed Siponimod Ponesimod AZD5904 Peg IFNb 1a IFNb-1b Fingolimod GRC4039 IFNb-1a im Natlizumab IFNb-1a sc CCX-140 Laquinimod Azathioprine Immune Novantrone BG12 AIN457 Teriflunomide GA Daclizumab regulation Antiproliferative Secukinumab agents THC:CBD NI-0801 Cladribine GA generics x2 4-AP Pixantrone GA 40 tiw IPX-056 Alemtuzumab RPI-78M Ocrelizumab ATX-MS-1467 Ofatumumab Nerispirdine PI2301 LY-2127399 Vaccine, RTL1000 Symptomatic Tx tolerization Belimumab = Oral administration Cytolytic mAbs = Injectable mAb, monoclonal antibody; Tx, treatment Evolving Treatment Landscape in MS RRMS Progressive MS (SPMS/PPMS) Generic/Biosimilar RRMS mAb Firategrast Fingolimod MD1003 Orals Teriflunomide Next Gen Fingolimod Laquinimod S1pRA Dimethyl Next Gen Fumarate Masitinib Siponimod Fumarates Approved 2013 2014 2015 2016 2017 2018+ 1st Line GA GA 3TW Tcelna Injectables Is there still aPeg IFNroleb1a for the IFNb1a Biosimilar IFNb1b Interferon-b injectablesGeneric GA? ? Mitoxantrone Natalizumab Alemtuzumab Daclizumab Ocrelizumab Ofatumumab mAbs Natalizumab Secukinumab Anti-LINGO1 Remyelination rHIgM22 GSK239512 Tiers of Treatment First line IFNβ-1a, IFNβ-1b, GA, teriflunomide, DMF Second line Fingolimod, natalizumab, alemtuzumab, daclizumab Third line Alemtuzumab, mitoxantrone, cladribine (IV), cyclophosphamide Experimental/ Ocrelizumab, (rituximab), ofatumumab, unproven bone marrow transplant therapies The “Lure” of Oral Therapies Convenience Ease of use Adherence But….. New concerns re: side effects – First pass effects Long term safety unknown Compatibility with other meds for other conditions Comparing New to Old How do the new agents compare to the older ones in terms of efficacy? – In the absence of “head to head” studies is there any way to assess benefit? – As placebo groups today do better than treated groups from previous years, how do we compare “relative” efficacies? • NNT increases with lowered event risk – Is a 50% reduction in annualized relapse rate from 1 to 0.5 mean the same as from .3 to .15? – NNT would suggest not as NNT goes from 2 to 7. How do we factor in novel and different risks? Treatment Outcomes for RRMS Trials All agents licensed based on primary outcome of reducing relapses Secondary outcomes almost always included effect on EDSS progression and reducing MRI activity It is NOT possible to compare the outcomes across clinical trials owing to many differing factors: – Trial design (frequency of imaging, definitions) – Analysis of outcomes (3 vs. 6 month confirmed EDSS progression; MRI activity) – Behaviour of placebo group comparator Differences in Randomized Placebo Controlled Pivotal Trials over the Years IFN ß-1a Glatiramer IFN ß-1a Study (IFN ß-1b1 Natalizumab5 Fingolimod6 Cladribine7 30mcg im qw2 Acetate3 44mcg sc tiw4 Date 1988-1993 1990-1993 1991-1994 1994-1997 2001-2004 2006-2009 2005-2007 372 301 251 560 942 1272 1326 N 3 arms 2 arms 2 arms 2 arms 2 arms 3 arms 3 arms Relapse (yr1) PEP Relapse Disability Relapse Relapse Relapse Relapse Disability (yr2) Placebo ARR 1.27 0.82 0.91 1.28 0.73 0.4 0.33 Relapse 24h 48h? 48h 24h 24h 24h 24h definition EDSS range 0 – 5.5 1 – 3.5 0 – 5 0 - 5 0 - 5 0 – 5.5 0 – 5.5 EDSS 2.9 2.3 2.6 2.5 2.3 2.6 2.9 Revised 2005 Diagnosis Poser Poser Poser Poser McDonald McDonald McDonald 1) IFNb MSSG. Neurology. 1993;43(4):655-61. 2) Jacobs LD, et a. Ann Neurol. 1996;39(3):285-94. 3) Johnson KP, et al. Neurology. 1995;45(7):1268- 76. 4) PRISMS Study Group. Lancet. 1998;352(9139):1498-504. 5) Polman CH, et al. N Engl J Med. 2006;354(9):899-910. 6) Kappos L, et al. N Engl J Med. 2010;362(5):387-401. 7) Giovanonni G, et al. N Engl J Med. 2010;362(5):416-26. ARR – Placebo Rates Reduce Over Time 1992-2002 2003-2011 1.5 1 ARR 0.5 0 Slide courtesy of Dr. Ron Milo, M.D. Comparison of Main Outcome Measures in Established Treatments IFNb-1b 250mg IFNb-1a 30mg im IFNb1a 44mg sc Glatiramer Acetate Study Agent sc eod1 qw2 tiw3 20mg sc od4 ARRR 34% 18% 32% 29% Absolute RRR 0.43 0.15 0.41 0.4 Relative Reduction in new T2 & Gd+ MRI 83% 52% 78% 30% Activity Relative Reduction in EDSS 29%* 37% 30% 12%* Progression Absolute Reduction in Proportion 8%* 13% 11% 3%* Progressing *p= ns 1IFNB Study Group Neurol 1993; 43(4):655–61; 2Jacobs et al Ann Neurol 1996;39(3):285–9; 3PRISMS Study Group Lancet 1998;352(9139):1498–504; 4Johnson et al Neurology 1995;45(7):1268–76 Comparison of Main Outcome Measures in More Recent Treatments Dimethyl Study Agent Natalizumab Fingolimod Teriflunomide Fumarate ARRR 68% 54% 31% 53% Absolute RRR 0.5 0.22 0.17 0.19 Relative Reduction in 83% 74% 85%* 67% new T2 & Gd+ 92% 82% 90%* MRI Activity Relative Reduction in 42% 30% 30% 38% EDSS Progression Absolute Reduction in 12% 6.4% 7.1% 11% Proportion Progressing *MRI studies performed on 43% of patients Interferon-b IFNb-1b sc IFNb-1a sc, IM Potential IFN-b action sites in MS BDNF NGF FcR CD8 gdT Ab+C9neo CTL Oligo NO Pl CD8 Oi TNFa CTL CD8 MMP Reg Oi EBV Glutamate IFNg B TNF Tr1 IL-10 Th2 Neut TGFb Th3 B7 CD28 MCP-1 IL-17 Th1 MIP-1a IP-10 RANTES Th17 Treg CD40 CD40L Foxp3 Astrocyte BBB IL-17 ICAM-1 VCAM-1 IL-23 Treg MMP-2/9 Foxp3 IFN IL-4 Tr1 Th17 g IL-5 Th2 LFA-1 IL-10 Th17 IL-6 VLA-4 TNF B Th3 CD8p Th1 IL-13 TGFb IL-6 & TGFß Treg BAFF APRIL IL-4 & IL-10 Foxp3 B7 CD28 TGFß TACI IL-12 B7 CD28 APC CD4 CD4+CD25+ CD4 HLA APC APC CD4 Thp TCR Myelin Ag Thp CD40 CD40L Thp Courtesy of S. Dhib-Jalbut Microbial Ag CD40 CD40L Change in Efficacy Responses over time in IFN-b 1a im MS trials 0,8 0,67 0,64 0,6 0,4 0,33 0.30 0,26 0,2 Annualized Annualized relapse rate 0,0 MSCRG EVIDENCE TRANSFORMS BRAVO COMBI-Rx IFN b-1a im 1993 2011 MSCRG Jacobs LD et al. Ann Neurol 1996;39:285–94; EVIDENCE Panitch H et al. Neurology 2002;59:1496-506; TRANSFORMS Cohen JA et al. N Engl J Med 2010;362:402-15; BRAVO Vollmer TL et al. J Neurol. 2014 261(4):773-83 ; COMBI Rx Lublin FD et al. Ann Neurol. 2013 73(3):327-40 Change in Efficacy Responses over time in IFN-b 1a sc MS trials 1,0 0,87 0,8 0,77 0,6 0,54 0,39 0,4 0,34 0.30 0,292 0,29 0,2 Annualized Annualized relapse rate 0,0 IFN b-1a sc 1994 2015 PRISMS Lancet 1998;352:1498–504; OWIMS Neurology 1999;53:679–86; EVIDENCE Panitch H et al. Neurology 2002;59:1496-506; EVIDENCE; The CAMMS223 N Engl J Med 2008;359:1786-801; Mikol DD et al. Lancet Neurol 2008;7:903– 14; CARE MS 1 Cohen JA et al. Lancet. 2012 380(9856):1819-28; Opera I,II (reviewed in Menge T et al. Expert Rev Neurother. 2016 Sep 1:1-9) Change in Efficacy Responses over time in IFN-b 1b MS trials 1,0 0,84 0,8 0,6 0,4 0,36 0,37 0,2 Annualized Annualized relapse rate 0,0 IFN β-1b BEYOND BECOME IFN b-1b 1988 2007 The IFNβ Multiple Sclerosis Study Group. Neurology 1993;43:655–61; O’Connor PW et al. Neurology 2006;66:894–900; BECOME Cadavid D et al. Neurology. 2009 72(23):1976-83 Glatiramer Acetate (GA) Glu – Ala – Tyr - Lys GA-Mechanism of Action GA-T cells CD8 (Th1 & Th2) GA-Th2 cells 1-3M Th2 Th2 Cross reactive T Myelin Ag Treg TcR T reg Bystander GA FOXP3 BDNF Myelin DR Suppression NTs Ag X Th2/Th3 X cytokines My X My (IL-10, Neuron APC TGFß) GA Th1 IL-27 type-2 Autoreactive Bystander Th1 cell My IL-10 Suppression Anergy Periphery Apoptosis BBB CNS Dhib-Jalbut, S. Pharmacol Ther. 2009 121(2):147-59 Change in Efficacy Responses over time in GA MS trials 0.8 0.59 0.6 0.4 0.34 0.29 0.29 0.23 0.2 Annualized rate relapse Annualized 0.0 Johnson REGARD BEYOND CONFIRM COMBI Rx 1991 2013 Johnson KP et al. Neurology 1995;45:1268–76; Mikol DD et al. Lancet Neurol 2008;7:903–14; O’Connor PW et al. Neurology 2006;66:894–900; Fox RJ N Engl J Med. 2012;367:1087–97; COMBI Rx Lublin FD et al.
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