Νεότερα Θεραπευτικά Δεδομένα στην Πολλαπλή Σκλήρυνση Δρ Μάριος Παντζαρής, Ανώτερος Νευρολόγος, Διευθυντής Γ Νευρολογικής Κλινικής, Αναπλ. Καθηγητής, Σχολή Μοριακής Ιατρικής, Ινστιτούτο Νευρολογίας και Γενετικής Κύπρου 4-5 Ιουνίου 2016 1
Disclosures Δηλώνω ότι έχω λάβει χορηγία υπό τη μορφή κάλυψης εξόδων συνεδρίων, συμμετοχής σε συμβουλευτικά σώματα, εκπαιδευτικά σεμινάρια, ομιλίες σε δορυφορικά συμπόσια και ενίσχυσης ερευνητικών προγραμμάτων από τις πιο κάτω φαρμακευτικές εταιρίες: Bayer Genesis Pharma (Greece, Cyprus) Merck-Serono Novagem (Cyprus) 4-5 Ιουνίου 2016 2
Φυσική Πορεία Νόσου: RRMS 20 30 years* 8 11 years* 14 20 years* EDSS 3.0 EDSS 6.0 EDSS 7.0 Mild-to-moderate disability; patients remain able to walk Cane required for walking Wheelchair required *Median number of years from first relapse. EDSS=Expanded Disability Status Scale; RRMS=relapsing-remitting multiple sclerosis. Compston A, et al, eds. McAlpine s Multiple Sclerosis. 4th ed. London, England: Churchill Livingstone; 2005; Confavreux C, et al. N Engl J Med. 2000;343(20):1430-1438; Ebers GC, et al. J Neurol. 2006;253(suppl 6):VI/3-VI/8; Weinshenker BG, et al. Brain. 1989;112(Pt 1):133-146. 4-5 Ιουνίου 2016 3
Κλινική πορεία- Βαθμός αναπηρίας Κλίμακα EDSS 10.0 9.5 0.0 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 4-5 Ιουνίου 2016 4
Phase 1 EDSS score Phase 2 Υπόθεση Δύο σταδίων στην Πολλαπλή Σκλήρυνση Διαφορετικά επίπεδα επιδείνωσης στην έναρξη ακολουθούνται από σταθερή επιδείνωση αργότερα 7 6 5 4 3 2 1 0 0 5 10 15 20 25 30 Χρόνια από την Έναρξη της Νόσου N=718 patients with MS who reached both EDSS 3 and EDSS 6. Phase 1: mean time from DSS 3 to DSS 6; Phase 2: mean time from multiple sclerosis clinical onset to DSS 3) 4-5 Ιουνίου 2016 Leray E et al. Brain 2010 5
Έγκαιρη έναρξη της θεραπείας Καθυστερημένη Θεραπεία Φυσική Πορεία Νόσου Καθυστερημένη Παρέμβαση Έναρξη Θεραπείας στη Διάγνωση Παρέμβαση στη Διάγνωση Έναρξη Νόσου Χρόνος 4-5 Ιουνίου 2016 6 J Manag Care Pharm. 2004;10(3)(suppl S-b):S4-S11
IFNβ Efficacy: Pivotal Studies Endpoint SC IFNβ-1b eod IM IFNβ-1a qw SC IFNβ-1a tiw Annualised relapse rate in RRMS Disability progression in RRMS 34 1 32 2, * 32 3 29 (NS) 1, 37 2, 24 4, Data is presented as percent (%) reduction vs placebo at 2 years. Conclusions regarding relative efficacy cannot be drawn from results of different clinical trials. General conclusion: IFNb therapies slow disease course by approximately one-third *For patients completing 2 years of treatment; sustained for 6 months; sustained for 3 months. SC=subcutaneous; eod=every other day; qw=once a week; tiw=three times a week. 1. IFN Mult Scler Study Group, Neurol.1993;43:655; 2. Jacobs LD et al. Ann Neurol. 1996;39:285; 3. PRISMS Study Group. Lancet.1998;352:1498; 4. Rebif EPAR - Scientific discussion 9/8/2006. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000136/human_med_001018.jsp&mid=wc0b01ac05800 1d124. 4-5 Ιουνίου 2016 7
CDMS (%) CDMS (%) Ολα τα ενέσιμα DMTs είναι αποτελεσματικά στη καθυστέρηση μετάπτωσης από CIS σε CDMS CDMS (%) CDMS (%) 50 40 30 20 Adjusted* HR=0.45, P<0.001 Risk Reduction: 55% IM IFNβ-1a Placebo IM IFNβ-1a 50 40 30 20 Adjusted HR=0.50, P<0.0001 Risk Reduction: 50% SC IFNβ-1b Placebo SC IFNβ-1b 10 10 0 1 4 7 10 13 16 19 22 25 28 Months SC IFNβ-1a 44 μg QW/TIW 31 34 37 50 Placebo Adjusted SC IFNβ-1a 44 μg QW QW: HR=0.53, P=0.0023 40 SC IFNβ-1a 44 μg TIW TIW: HR=0.48, P=0.0004 Risk Reduction: 47%/52% 30 0 50 40 30 0 180 360 540 720 Time (Days). Glatiramer Acetate Adjusted HR=0.55, P=0.0005 Risk Reduction: 45% Placebo GA 20 20 10 10 0 0 180 360 540 720 Time (Days) 0 0 180 360 540 720 Time (Days) *Adjusted for age, type of initial event, T2 lesion volume, and number of Gd+ lesions; adjusted for age, sex, type of initial event, steroid use, T2 lesion volume, and number of Gd+ lesions; adjusted for randomisation stratification factors; from HR over 3 years. DMT=disease-modifying therapy; IFNβ=interferon beta; HR=hazard ratio; CDMS=clinically definite MS; GA=glatiramer acetate. Kinkel RP et al. Presented at AAN; April 28 May 5, 2007; Boston, MA. P04.270; Kappos L et al. Neurology. 2006;67:1242-1249; Comi G et al. Lancet. 2009;374:1503-1511; Comi G et al. Presented at AAN; April 9 16, 2011; Honolulu, HI. P07.194. 4-5 Ιουνίου 2016 8
NEW ORAL ( FIRST LINE ) TREATMENTS 4-5 Ιουνίου 2016 9
LESS EFFICACY MORE Dimethyl Fumarate Teriflunomide First Line LESS SAFETY Glatiramer Acetate Interferons DMΤs MORE 4-5 Ιουνίου 2016 10
Dimethyl fumarate (Tecfidera) 4-5 Ιουνίου 2016 11
Nrf2 Μονοπάτι: Πιθανός μηχανισμός δράσης του Tecfidera DMF or MMF Keap1 Nrf2 Nrf2 Nrf2 Proteasome Nrf2 Nrf2 ARE Nucleus Αντι-οξειδωτική αντίδραση Αποτοξίκωση Αποκατάσταση του ενεργειακού μεταβολισμού Επιδιόρθωση/Διάσπαση πρωτεϊνών Αντι-οξειδωτικά ένζυμα Αντι-τοξικά ένζυμα Ένζυμα που παράγουν NADPH Άλλα βοηθητικά ένζυμα Cytoplasm Keap1=kelch-like ECH-associated protein 1; ARE=antioxidant response element, Nrf2= nuclear erythroid 2-related factor van Horssen J et al. Biochem Biophys Acta. 2011;1812:141-150; Linker RA et al. Brain. 2011;134:678-692. 4-5 Ιουνίου 2016 12
Adjusted Annualized Relapse Rate Proportion Relapsed Ενοποιημένη Ανάλυση: Ετησιοποιημένη συχνότητα υποτροπών και αναλογία ασθενών με υποτροπή 0,6 0,6 DMF bid=43% risk reduction, P 0.0001 DMF tid=47% risk reduction, P 0.0001 0,5 0,5 0.437 0,4 0,3 49% reduction vs placebo P 0.0001* 49% reduction vs placebo P 0.0001* 0,4 0,3 0.280 0,2 0,2 0.251 0,1 0,1 Placebo DMF bid DMF tid 0,0 Placebo (n=771) DMF bid (n=769) DMF tid (n=761) 0,0 BL 0 12 24 36 48 60 72 84 96 Time on Study (weeks) Integrated ITT population; only relapses confirmed by the INEC were included in the analysis. *P value based on Poisson regression (due to underdispersion using negative binomial distribution) adjusted for baseline EDSS score ( 2.0 vs >2.0), study, region, number of relapses in the 1 year prior to study entry, and baseline age (<40 vs 40 years); P value based on Cox proportional hazards model; Kaplan-Meier estimate of the proportion of subjects relapsed within 2 years. BL=baseline; ITT=intention-to-treat; INEC=independent neurology evaluation committee. Gold R et al. Presented at ECTRIMS; October 10 13, 2012; Lyon, France. S151. 4-5 Ιουνίου 2016 13
Proportion of Subjects with Sustained Disability Progression Ενοποιημένη ανάλυση: Εξέλιξη της αναπηρίας που παραμένει για 12 και 24 εβδομάδες* Εξέλιξη της αναπηρίας (12-εβδομάδες) Εξέλιξη της αναπηρίας (24-εβδομάδες) 0.3 DMF bid=32% risk reduction, P=0.0034 DMF tid=30% risk reduction, P=0.0059 0.3 DMF bid=29% risk reduction, P=0.0278 DMF tid=32% risk reduction, P=0.0177 0.2 Placebo DMF bid DMF tid 0.222 0.155 0.2 Placebo DMF bid DMF tid 0.148 0.1 0.146 0.1 0.105 0.104 0 BL 12 24 36 48 60 72 84 96 Time on Study (weeks) 12 24 36 48 60 72 84 96 Time on Study (weeks) Pooled ITT population. *Sustained progression of disability was defined as at least a 1.0-point increase on the EDSS from a baseline EDSS score 1.0 sustained for 12 weeks or at least a 1.5-point increase on the EDSS from a baseline EDSS score of 0.0 sustained for 12 weeks; P value based on a stratified Cox proportional hazards model; Kaplan- Meier estimate of the proportion of subjects sustained progression within 2 years. BL=baseline; ITT=intention-to-treat. Gold R et al. Presented at ECTRIMS; October 10 13, 2012; Lyon, France. S151. 4-5 Ιουνίου 2016 14 0 BL
Patients Free of Measured Disease Activity (%) Ενοποιημένη ανάλυση: Ελευθερία μετρήσιμης δραστηριότητας νόσου 30 25 20 OR 2.7 (1.7 4.3) P<0.0001 OR 2.6 (1.6 4.1) P<0.0001 23 23 Placebo DMF bid DMF tid 15 10 11 5 0 n= 309 299 296 P values are for comparisons with placebo and are from a logistic regression model adjusted for baseline EDSS score, age (<40 vs 40), region, number of relapses in the year prior to study entry, baseline volume of T2 lesions, and baseline number of Gd+ lesions. OR=odds ratio (95% confidence intervals). Havrdova et al. Presented at AAN; March 16 23, 2013; San Diego, CA, USA. P07.106. 4-5 Ιουνίου 2016 15
Patients (%) Patients (%) Επίπτωση γαστρεντερολογικών συμβαμάτων και ερυθρίασης 35 30 25 20 15 10 5 0 35 30 25 20 15 10 5 0 Flushing Events* Placebo (n=408) DMF bid (n=410) DMF tid (n=416) 1 2 3 4 5 6 7 8 9 10 11 12 24 Month Gastrointestinal (GI) Events 1 2 3 4 5 6 7 8 9 10 11 12 24 Month *Flushing events included the preferred terms flushing, hot flush, erythema, generalised erythema, burning sensation, skin burning sensation, feeling hot, and hyperemia ; gastrointestinal events included the preferred terms in the level 2 subordinate standardised MedDRA queries gastrointestinal nonspecific inflammations or gastrointestinal nonspecific symptoms and therapeutic procedures. Selmaj K et al. Presented at ECTRIMS; October 10 13, 2012; Lyon, France. P484. 4-5 Ιουνίου 2016 16
Γαστρεντερολογικά συμβάματα και ερυθρίαση: Στρατηγικές αντιμετώπισης Σύμφωνα με διαθέσιμες πληροφορίες Λήψη με τροφή Έναρξης θεραπείας με δοσολογία 120mg για 7 ημέρες Χορήγηση ασπιρίνης 325 mg χωρίς εντερική επικάλυψη, 30 λεπτά πριν από το Tecfidera, για διάστημα χορήγησης δόσης 4 ημερών Μείωση δόσης σε 120mg μέχρι ένα μήνα (σε εμμένουσα συμβάματα) 4-5 Ιουνίου 2016 17
Ενοποιημένη ανάλυση ασφάλειας: Συνήθεις ΑΕ ( 10% σε κάθε ομάδα) Event, n (%) Indicates 3% higher incidence in either dimethyl fumarate group vs placebo. Placebo (n=836) DMF bid (n=769) DMF tid (n=823) Any adverse event 769 (92) 733 (95) 767 (93) Flushing 39 (5) 265 (34) 240 (29) MS relapse 360 (43) 221 (29) 211 (26) Nasopharyngitis 169 (20) 170 (22) 179 (22) Headache 137 (16) 133 (17) 138 (17) Diarrhea 86 (10) 107 (14) 136 (17) Urinary tract infection 96 (11) 107 (14) 95 (12) Upper respiratory tract infection 88 (11) 99 (13) 101 (12) Nausea 72 (9) 93 (12) 115 (14) Fatigue 91 (11) 94 (12) 103 (13) Back pain 92 (11) 94 (12) 84 (10) Abdominal pain upper 47 (6) 76 (10) 94 (11) Proteinuria* 59 (7) 67 (9) 85 (10) The overall incidence of any GI event was 31%, 40%, and 43% in the placebo, dimethyl fumarate bid, and dimethyl fumarate tid groups, respectively; *no notable differences in levels of BUN and creatinine, urine β2-microglobulin, and urine microalbumin were observed across treatment groups with monitoring every 4 weeks.gi=gastrointestinal; BUN=blood urea nitrogen. Selmaj K et al. Presented at ECTRIMS; October 10 13, 2012; Lyon, France. P484. 4-5 Ιουνίου 2016 18
Εγκυμοσύνη Dimetyl Fumarate (Tecfidera) Οι μελέτες σε ζώα έδειξαν πως ο διμέθυλ -φουμαρικός εστέρας δεν συσχετίστηκε με τερατογένεση 56 εγκυμοσύνες αναφέρθηκαν μέχρι σήμερα στις κλινικές μελέτες Παρόλο που τα στοιχεία είναι περιορισμένα η αναλογία των γεννήσεων ήταν παρόμοια μεταξύ του διμέθυλ-φουμαρικού (65%) και του placebo (64%) Δεν υπάρχουν στοιχεία που να δείχνουν αυξημένο κίνδυνο για δυσπλασίες ή αποβολές με την έκθεση κατά το πρώτο τρίμηνο της εγκυμοσύνης στο διμέθυλ-φουμαρικό Pregnancy Data as of Jan 2, 2013 1 Placebo DMF GA Number of pregnancies in dimethyl fumarate clinical trials 14 38 4 Known outcomes 14 34 3 Live birth* 9 (64%) 22 (65%) 1 Spontaneous abortion 3 (21%) 3 (8%) 0 Elective termination 2 (14%) 9 (26%) 2 4-5 Ιουνίου 2016 *No fetal abnormalities were reported for any of the live births; the rates of spontaneous abortion are within the expected range for the general population (12% 22%). 2 1. Gold et al. Presented at AAN; March 16 23, 2013; San Diego, CA. P02.129; 2. García-Enguídanos A et al. Eur J Obstet Gynecol Reprod Biol. 2002;102:111-119. 19
Teriflunomide 4-5 Ιουνίου 2016 20
Τεριφλουνομίδη Leflunomide Teriflunomide Η Τεριφλουνομίδη είναι ο ενεργός μεταβολίτης της λεφλουνομίδης που είναι εγκεκριμένη για την αντιμετώπιση της ρευματοειδούς αρθρίτιδας (εμπειρία 2 εκ. έτη ασθενών) Η Τεριφλουνομίδη επιλέχθηκε να αναπτυχθεί στην ΠΣ - Για να αποφευχθούν οι ανεπιθύμητοι μεταβολίτες της λεφλουνομίδης - Για να αποφευχθεί ο ηπατικός μεταβολισμός της λεφλουνομίδης σε τεριφλουνομίδη - Για να μειωθεί η εμπλοκή του CYP450 συγκριτικά με την λεφλουνομίδη το οποίο μπορεί να μειώσει δυνητικά κλινικά σημαντικές αλληλεπιδράσεις με άλλα φάρμακα 4-5 Ιουνίου 2016 CYP450, cytochrome P450 21 1. Genzyme/Sanofi data on file; 2.Wang et al. Eur J Neurol 2011;18(Suppl 2):268
Τεριφλουνομίδη Προτεινόμενος μηχανισμός Δράσης στην ΠΣ Immune system Αναστέλλει επιλεκτικά και αναστρέψιμα την διϋδροοροτική αφυδρογονάση (DHODH), ένα σημαντικό ένζυμο στην de novo σύνθεση των πυριμιδινών που είναι απαραίτητη στα ταχέως διαιρούμενα λεμφοκύτταρα Resting lymphocytes Stimulated myelinspecific lymphocytes Αναστέλλει τον πολλαπλασιασμό και την ενεργοποίηση διεγερμένων Τ και Β λεμφοκυττάρων στην περιφέρεια που είναι διαθέσιμα να μεταναστεύσουν στο ΚΝΣ και φέρονται ως υπεύθυνα για την ζημιογόνα φλεγμονώδη διεργασία στην ΠΣ Basal demand for pyrimidine nucleotides Increased demand for pyrimidine nucleotides DHO-DH TERIFLUNOMIDE Η σύνθεση των πυριμιδινών μέσω της οδού διάσωσης στα βραδέως διαιρούμενα ή σε φάση ανάπαυσης κύτταρα δεν επηρεάζεται Διατηρείται η φυσιολογική ανοσολογική Alternative "Salvage" pathway XDe novo pathway επιτήρηση Immune surveillance X Pro-inflammatory and protective autoimmune immune responses response DHODH = dihydroorotate dehydrogenase 4-5 Ιουνίου 2016 22 Gold and Wolinsky. Acta Neurol Scand 2011;124:75 84
Annualized Relapse Rate Annualized Relapse Rate Η Τεριφλουνομίδη Μείωσε την Συχνότητα των Υποτροπών vs. Placebo TEMSO 1 TOWER 2 0,6 0.6 0,5 0,4 0,3 0,54 RRR: 31% p<0.001 0,37 0,37 0.5 RRR: 22% RRR: 31% 0.50 p=0.0183 p<0.001 0.4 RRR: 36% 0.39 p=0.0001 0.3 0.32 0,2 0.2 0,1 0.1 0,0 0.0 Placebo 7 mg 14 mg Placebo 7 mg 14 mg n=363 n=365 n=358 n=388 n=407 n=370 RRR=relative risk reduction, σχετική μείωση του κινδύνου 4-5 Ιουνίου 2016 23 1. O'Connor P et al. N Engl J Med 2011;365:1293-303;.2.Confavreux C, et al. Lancet Neurol 2014.
Sustained Disability Progression (%) Sustained Disability Progression (%) Η Τεριφλουνομίδη 14 mg Μείωσε Σημαντικά τον Κίνδυνο Εξέλιξης της Αναπηρίας vs. Placebo TEMSO 1 TOWER 2 40 7 mg vs. placebo: HR 0.763, p=0.0835 14 mg vs. placebo: HR 0.702, p=0.0279 40 7 mg vs. placebo: HR 0.955, p=0.7620 14 mg vs. placebo: HR 0.685, p=0.0442 30 20 Teriflunomide 14 mg Teriflunomide 7 mg Placebo 27% 22% 20% 30% Μείωση κινδύνου P<0,05 30 20 Teriflunomide 14 mg Teriflunomide 7 mg Placebo 22% 21% 16% 32% Μείωση κινδύνου P<0,05 10 10 0 0 12 24 36 48 60 72 84 96 108 Weeks 0 0 12 24 36 48 60 72 84 96 108120132 Weeks HR=hazard ratio 4-5 Ιουνίου 2016 24 1. O'Connor P et al. N Engl J Med 2011;365:1293-303, 2. Confavreux C, et al. Lancet Neurol 2014.
Disability Progression Confirmed for 12 Weeks (%) Annualized Relapse Rate Η Τεριφλουνομίδη στην Υποομάδα ασθενών με υψηλής ενεργότητας νόσο 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 40 35 30 25 20 15 10 5 ARR 0.728 Placebo 12-week SAD 31% Risk reduction (p<0.001) Teriflunomide 7 mg Teriflunomide 14 mg 0.499 0.484 Teriflunomide 7 mg Risk reduction 29% 46% 34% Risk reduction (p=0.001) Teriflunomide 14 mg p value 0.088 0.004 Placebo Teriflunomide 7 mg Teriflunomide 14 mg 31% 23% TEMSO/TOWER Συνδυασμένη ανάλυση Υψηλής ενεργότητας νόσος: 2 υποτροπές/έτος πριν από την ένταξη στην μελέτη 0 0 12 24 36 48 60 72 84 96 108 120 132 Weeks 4-5 Ιουνίου 2016 25 18% Kappos L et al. ECTRIMS 2012, S0153.
Change From Baseline, Median, % TEMSO Η τεριφλουνομίδη μειώνει σημαντικά την εγκεφαλική ατροφία 0 Annualized Percentage Change in Brain Volume -0,2-0,4 36.9% reduction P=0.0001-0,6-0,8 30.6% reduction P=0.0001-1 -1,2-1,4 Placebo Teriflunomide 14 mg 0 1 2 Year 4-5 Ιουνίου 2016 Teriflunomide 7 mg vs placebo at Year 1: 34.4% reduction, P=0.0011; Year 2: 27.6% reduction, P=0.0019 A SIENA analysis of the TEMSO MRI dataset Late breaking news ECTRIMS 2015 26
Neurology 2016;86:920 930 4-5 Ιουνίου 2016 27
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Συχνές κοινές παρενέργειες TEMSO TOWER Placebo Teriflunomide Placebo Teriflunomide Adverse Event, % (n=360) 7 mg (n=368) 14 mg (n=358) (n=385) 7 mg (n=409) 14 mg (n=371) Diarrhea 8.9 14.7 17.9 7.3 12.0 11.1 Nausea 7.2 9.0 13.7 8.8 8.3 10.2 Elevated ALT 6.7 12.0 14.2 8.3 11.2 14.0 Hair thinning/ decreased hair density Hypersensitivity or skin disorders 3.3 10.3 13.1 4.4 10.3 13.5 7.2 10.3 11.2 Not Reported Less than 1% of patients discontinued treatment due to hair loss or thinning and 85% recovered without sequelae; most diarrhea and nausea occurred in the first 3 months of the study and resolved without intervention. O Connor PW et al. N Engl J Med. 2011;365:1293-1303; Kappos L et al. MS Presented at ECTRIMS; October 10 13, 2012; Lyon, France. P153. Freedman MS et al. Presented at CMSC ACTRIMS; May 30 June 2, 2012: San Diego, CA. P7; Freedman MS et al. Presented at CMSC ACTRIMS; May 30 June 2, 2012: San Diego, CA. P8. 4-5 Ιουνίου 2016 30
Εγκυμοσύνη In animal studies, teriflunomide has been shown to be teratogenic and embryolethal when administered during pregnancy at doses used clinically 80 pregnancies have been reported in teriflunomide clinical trials to date All subjects were instructed to undergo an immediate accelerated elimination procedure with cholestyramine or activated charcoal. Mean elimination time of 11 days (range 5 17) to achieve plasma levels of <0.02 mg/l in 2 tests 14 days apart No fetal abnormalities were reported in the 21 live births in teriflunomide-treated patients Pregnancy Data as of 2012 Placebo Teriflunomide IFNb-1a Number of pregnancies in Teriflunomide clinical trials 9 69 2 Known outcomes 9 62* 2 Live birth 2 (22%) 21 (34%) 2 Spontaneous abortion 1 (11%) 13 (21%) 0 Elective termination 6 (67%) 28 (45%) 0 *Seven pregnancies were still ongoing; the rates of elective termination were high. Brent RL. Teratology 2001;63:106-112; Kieseier B et al. Presented at ECTRIMS; October 2-5, 2013; Copenhagen, Denmark. 4-5 Ιουνίου 2016 31
LESS EFFICACY MORE Natalizumab JC Virus Second Line Fingolimod Dimethyl Fumarate First Line- 2 nd Choice Teriflunomide First Line Interferons Glatiramer Acetate LESS SAFETY MORE 4-5 Ιουνίου 2016 32
Dimethyl fumarate (Tecfidera) 4-5 Ιουνίου 2016 33
4-5 Ιουνίου 2016 34 Fernandez O. P3.339, AAN, Washington April 2015
Adjusted Annualized Relapse Rate (95% CI) Tecfidera - Αποτελεσματικότητα βάσει προηγούμενης θεραπείας 0.5 0.4 Annualized Relapse Rate at 2 Years by Subgroup Placebo DMF 240 mg bid DMF 240 mg tid 0.3 0.2 0.1 0 0.35 0.16 0.16 0.37 0.22 0.18 0.38 0.23 0.16 n=397 n=398 n=393 n=221 n=202 n=193 n=164 n=155 n=145 Treatment-Naive Any ABCR 1 ABCR ABCR=Avonex, Betaseron, Copaxone, Rebif ; CI=confidence interval. Hutchinson M et al. Presented at AAN; March 16 23, 2013; San Diego, CA, USA. P07.128 4-5 Ιουνίου 2016 35
Teriflunomide 4-5 Ιουνίου 2016 36
Τεριφλουνομίδη 14mg: Αποτελεσματικότητα στην μείωση των υποτροπών στις υποομάδες ασθενών TEMSO & TOWER Pooled Subgroup Comparison Relative risk (95% CI) Placebo Worse Placebo Better Gender Male (N=639) 14mg vs Placebo 0.735 (0.555, 0.974) Female (N=1612) 14mg vs Placebo 0.635 (0.529, 0.762) Baseline EDSS score EDSS score 3.5 (N=1705) 14mg vs Placebo 0.615 (0.512, 0.739) EDSS score >3.5 (N=546) 14mg vs Placebo 0.795 (0.607, 1.040) No. of relapses in past 2 years 1 (N=602) 2 (N=1028) 14 mg vs Placebo 0.566 (0.397, 0.806) 14 mg vs Placebo 0.662 (0.532, 0.824) 3 (N=397) 14 mg vs Placebo 0.599 (0.439, 0.819) 4 (N=222) 14 mg vs Placebo 0.809 (0.546, 1.197) MS subtype Secondary progressive and progressive relapsing (N=122)14 mg vs Placebo 1.086 (0.531, 2.221) Relapsing remitting (N=2127) 14 mg vs Placebo 0.646 (0.553, 0.754) Previous DMT use Yes (N=683) 14 mg vs Placebo 0.680 (0.534, 0.865) No (N=1568) 14 mg vs Placebo 0.641 (0.527, 0.779) 4-5 Ιουνίου 2016 14 mg vs placebo Genzyme/sanofi data on file.. 0.125 0.250 0.5 1.0 2.0 4.0 Statistics: Relative Risk 37
TEMSO: Treatment-Naïve vs. Previously Treated Patients Annualized Relapse Rate Favors teriflunomide Favors placebo Disability Progression Favors teriflunomide Favors placebo Prior use of DMT in last 2 yrs Yes (n=294) No (n=792) TOTAL POPULATION 0.12 5 0.25 0.5 1.0 2.0 Relative risk 4.0 0.062 0.12 0.25 0.5 1.0 2. 5 5 0 Relative risk 4.0 Teriflunomide 7 mg Teriflunomide 14 mg Miller A et al. Mult Scler 2012;18:1625 32. 38
Natalizumab (Tysabri) 4-5 Ιουνίου 2016 39
In the Inflammatory Process, Natalizumab Could Intervene at Multiple Points 1. Leukocyte migration from blood to tissue Natalizumab 2. Leukocyte priming and activation 3. Modulation of leukocyte apoptosis Natalizumab VCAM-1=vascular cell adhesion molecule 1. 1. Cannella B et al. Ann Neurol. 1995;37:424-435; 2. TYSABRI [prescribing information]. Cambridge, MA: Biogen Idec; 2012; 3. Yednock TA et al. Nature. 1992;356:63-66; 4. TYSABRI [EMA product information]. Denmark: Biogen Idec A/S; 2012. 4-5 Ιουνίου 2016 40
ARR (95% CI) AFFIRM - Ετήσια συχνότητα υποτροπών 68% Μείωση στην ετήσια συχνότητα υποτροπών 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0.73 Years 0 2 P<0.001 0.23 68% 0.78 `` P<0.001 0.27 66% 0.67 Placebo n=315 Natalizumab n=627 0.20 Year 0 1 Year 1 2 P<0.001 FDA per-subject mean relapse rate at 2 years = 0.67 for placebo and 0.22 for natalizumab (67% reduction) ARR=annualized relapse rate; CI=confidence interval. 4-5 Ιουνίου 2016 Polman CH et al. N Engl J Med. 2006;354:899-910; Polman CH et al. Presented at AAN; April 9 16, 2005; Miami, FL. 41 70%
Ποσοστό με επιβεβαιωμένη επιδείνωση Ποσοστό με επιβεβαιωμένη επιδείνωση AFFIRM - Πιθανότητα εξέλιξης της αναπηρίας Μείωση κατά 42% 54% vs. Placebo Παραμένει για 3 μήνες Παραμένει για 6 μήνες 0.4 Hazard ratio=0.58 P<0.001 0.4 Hazard ratio=0.46 P<0.001 0.3 0.2 Placebo 29% 42% 0.3 0.2 Placebo 23% 54% 0.1 TYSABRI 17% 0.1 TYSABRI 11% 0.0 0.0 0 12 24 36 48 60 72 84 96 108 120 Week 0 12 24 36 48 60 72 84 96 108 120 Week Placebo TYSABRI Number of Patients at Risk 315 296 283 264 248 240 229 216 208 200 627 601 582 567 546 525 517 503 490 478 199 473 Placebo TYSABRI Number of Patients at Risk 315 298 287 269 253 246 237 225 216 211 627 611 594 581 559 540 532 521 509 503 211 502 4-5 Ιουνίου 2016 42 Polman CH, et al. N Engl J Med. 2006;354:899-910. AFFIRM Study
Reduction (%) Reduction (%) AFFIRM - Ασθενείς με υξηλής δραστηριότητας ΠΣ (>2 Relapses and Gd+ Lesions at Baseline) Annualised Relapse Rate Reduction* Reduction in Risk of 12-Week (3-Month) Sustained EDSS Progression 81% (P<0.001) 53% (P=0.029) *Natalizumab annualised relapse rate reduction vs placebo: 0.28 vs 1.46; EDSS progression calculated from 1 HR, 1 0.47 for natalizumab. TYSABRI (natalizumab) [summary of product characteristics]. Maidenhead, Berkshire, UK: Biogen Idec Ltd; October 2013; Hutchinson M et al. J Neurol. 2009;254:405-415 & 1035-1037. 4-5 Ιουνίου 2016 43
Percentage of Patients (%) Percentage of Patients (%) Freedom from Disease Activity/Disease Activity Free: Post hoc analysis of patients with no relapses, no sustained (12-week) disability progression, no Gd+ lesions, no new or enlarging T2-hyperintense lesions Overall at 2 years: 37% natalizumab vs 7% placebo (P<0.0001) 100 80 60 Placebo Natalizumab 100 P<0.0001 P<0.0001 P<0.0001 P<0.0001 70 80 65 51 60 40 40 34 20 0 18 15 Year 0 1 Year 1 2 Non-Highly Active Disease <2 relapses in past 12 months or no Gd+ lesions at study entry 20 0 3 4 n=248 n=458 n=228 n=407 n=59 n=146 n=56 n=137 Year 0 1 Year 1 2 Highly Active Disease 2 relapses in past 12 months and 1 Gd+ lesion at study entry 4-5 Ιουνίου 2016 44 Lancet Neurol. 2009;8:254-226.
Βελτίωση της αναπηρίας EDSS Στοιχεία από την AFFIRM Πιθανότητα βελτίωσης της αναπηρίας κατά 1 βαθμό EDSS Tysabri 29,6% Placebo 18,7% Αύξηση πιθανότητας 69% Πιθανότητα βελτίωσης της αναπηρίας κατά 1 βαθμό EDSS σε ασθενείς με υψηλής δραστηριότητας νόσο ((>2 Relapses and Gd+ Lesions at Baseline) Tysabri 35,5% Placebo 15,4% Αύξηση πιθανότητας 143% Munschauer F et al. Presented at ECTRIMS; September 17 20, 2008: Montréal
Η έγκαιρη έναρξη του Tysabri αναστέλλει τη μακροχρόνια εξέλιξη της αναπηρίας TOP 1 : Ανάλυση υποομάδων 1. TOP: Tysabri Observational Program 4-5 Ιουνίου 2016 46 Kappos L et al. Presented at ENS; June 9 12, 2012; Prague, Czech Republic. O261.
Kίνδυνοι με τη χρήση Natalizumab Hypersensitivity PML Suspend dosing Often associated with anti-natalizumab antibodies Risk stratification by anti-jcv antibody testing TYSABRI (natalizumab) [summary of product characteristics]. Maidenhead, Berkshire, UK: Biogen Idec Ltd; October 2013. 4-5 Ιουνίου 2016 47
Παρακολούθηση ασθενών χρησιμοποιώντας τα αντισώματα έναντι του ιού JC- Κίνδυνος εκδήλωσης PML Anti-JCV Antibody Status Negative Positive 0.1/1000 Risk is similarly low, regardless of exposure time or prior IS treatment Reliability of the STRATIFY-JCV assay as a risk management tool: For patients with natalizumab-associated PML and a blood sample taken more than 6 months prior to diagnosis, anti-jcv antibodies were detected in 99% cases (n=174) Medical information website. Boston, MA, USA: Biogen Idec Inc. https://medinfo.biogenidec.com/medinfo. Accessed August 5, 2013. JCV=JC virus; PML=progressive multifocal leukoencephalopathy. 4-5 Ιουνίου 2016 48
Διαβάθμιση Κινδύνου PML Anti-JCV Antibody Status Negative Positive Prior IS Use Natalizumab Exposure No No Prior IS Use Yes Prior IS Use 0.1/1000 95% CI: 0.01 0.35 1 24 months 25 48 months 49 72 months 0.7/1000 49 95% CI: 0.5 1.0 5.3/1000 95% CI: 4.4 6.2 6.1/1000 95% CI: 4.8 7.8 1.8/1000 95% CI: 1.1 2.7 11.2/1000 95% CI: 8.6 14.3 Insufficient data. Data beyond 6 years of treatment are limited. Data are insufficient to adequately determine PML risk in anti-jcv antibody-positive patients with prior IS use and >48 months of natalizumab exposure. 4-5 Ιουνίου 2016
Υπολογισμός κίνδυνου της PML, με τη χρήση του INDEX σε ασθενείς χωρίς IS Index Threshold 0.9 PML Risk Estimates (95% CI) per 1000 Patients (No Prior IS Use) 1 24 Months 25 48 Months 49 72 Months 0.1 (0 0.41) 0.3 (0.04 1.13) 0.4 (0.01 2.15) 1.1 0.1 (0 0.34) 0.7 (0.21 1.53) 0.7 (0.08 2.34) 1.3 0.1 (0.01 0.39) 1.0 (0.48 1.98) 1.2 (0.31 2.94) 1.5 0.1 (0.03 0.42) 1.2 (0.64 2.15) 1.3 (0.41 2.96) >1.5 1.0 (0.64 1.41) 8.1 (6.64 9.8) 8.5 (6.22 11.38) 4-5 Ιουνίου 2016 50 Annals of Neurology 2014
4-5 Ιουνίου 2016 51
Σε ασθενείς που διαγνώστηκαν με PML σχετιζόμενη με τη χορήγηση Natalizumab, οι MRI 6 με 12 μήνες πριν τη διάγνωση δεν έδειξαν βλάβες που εξελίχθηκαν σε PML. Ωστόσο, στις MRI που πραγματοποιήθηκαν 1 με 6 μήνες πριν την διάγνωση της PML παρατηρήθηκαν συχνά μικρές βλάβες που εξελίχθηκαν σε PML. MRI Scan Early PML lesion seen on MRI Months 12 11 10 9 8 7 6 5 4 3 2 1 0 No lesion seen on MRI 6 12 months prior to diagnosis, there were no lesions that evolved into PML 1 6 months prior to diagnosis, small lesions that evolved into PML were observed frequently MRI at PML diagnosis* *PML diagnosis was the date JCV DNA was found in CSF or brain tissue, or PML was identified on MRI (according to Wiki database from MedWatch) in 141 patients. Biogen Idec, data on file. 52 Each Biogen Idec line function and country affiliate is responsible for Ensuring that the materials and their use comply with local and audience-specific legal and regulatory requirements Submission of all audience-specific materials (including any related communication materials) to the appropriate local approval process
Asymptomatic Progressive Multifocal Leukoencephalopathy Associated with Natalizumab: Diagnostic Precision with MR Imaging Hyperintensity on diffusion-weighted images and involvement of U fibers were the most predictive features (Green arrows) Punctate lesions are exclusively observed in patients with NTZ PML (red arrows) 4-5 Ιουνίου 2016 53 Radiology. 2015 Oct 5:150673. [Epub ahead of print]
4-5 Ιουνίου 2016 54
Fingolimod 4-5 Ιουνίου 2016 55
S1P Receptor Fingolimod is a sphingosine analogue that after phosphorylation functions as a modulator of S1PR1, S1PR3, S1PR4, and S1PR5. Interactions with S1PR1 and off -target interactions with other S1PR subtypes, particularly S1PR3, might mediate other potential adverse effects of fingolimod, including hypertension, macular oedema, pulmonary toxic effects, and hepatotoxicity 4-5 Ιουνίου 2016 56
Fingolimod Targets S1P Receptors, Which Are Widely Expressed throughout the Body Permeability of vessels in the eye Macular edema Smooth bronchial muscles Respiratory flow restriction Atrial myocytes Lowering heart rate Disturbed AV conduction Neural cells express S1P receptors known to modulate neuropathological processes relevant to MS Smooth vascular musculature Increased vascular tone Risk of elevated LFTs in 8%, usually early Blood Efferent Lymph S1P Gradient Lymphoid Organ Autoaggressive lymphocytes remain in the lymph nodes, away from the CNS reversible REDISTRIBUTION, not depletion S1P=sphingosine 1-phosphate; LFT=liver function test; >70% reduction in MS=multiple sclerosis; AV=atrioventricular; CNS=central nervous system. lymphocyte count, Adapted from Marsolais D, Rosen H. Nat Rev Drug Disc. 2009;8:297-307; 18% grade 4 Comi G et al. Mult Scler. 2010;16:197-207. 4-5 Ιουνίου 2016 57
Fingolimod also has differential effects on the trafficking and function of B-cell subtypes and natural killer (NK) cells in peripheral blood and the CNS. Fingolimod also crosses the blood brain barrier (BBB) and accumulates in the CNS. Experimental evidence increasingly supports a direct action of fingolimod within the CNS on brain cells, providing protection against the neurodegenerative component of RMS. 4-5 Ιουνίου 2016 58
Adjusted* Annualised Relapse Rate Adjusted* Annualised Relapse Rate Ετησιοποιημένος ρυθμός υποτροπών FREEDOMS 1 FREEDOMS II 2 0,5 0,5 0,4 0,3 0,2 0,4 54% reduction vs placebo P<0.001 0,18 60% reduction vs placebo P<0.001 0,16 0,4 0,3 0,2 0,4 48% reduction vs placebo P<0.001 0,21 0,1 0,1 0 n=418 n=425 n=429 Placebo Fingolimod 0.5 mg Fingolimod 1.25 mg 0 n=355 n=358 Placebo Fingolimod 0.5 mg *Adjusted for study group, region, number of relapses and EDSS score at baseline. 1. Kappos L et al. N Engl J Med. 2010;362:387-401. 2. 4-5 Ιουνίου 2016 Calabresi PA et al. Presented at AAN; April 21 28, 2012; New Orleans, LA, USA. ESS.015. 59
Sustained Disability Progression* (%) Sustained Disability Progression* (%) Εξέλιξη της αναπηρίας (12 εβδομάδες) FREEDOMS 1 FREEDOMS II 2 40 30 30 Placebo Fingolimod 0.5 mg HR=0.70; P=0.02 Fingolimod 1.25 mg HR=0.68; P=0.02 40 30 Placebo Fingolimod 0.5 mg HR=0.83; P=0.227 29.0% 25.3% 25 20 20 15 10 10 24.1% 17.7% 16.6% 27-31% reduction 20 10 13% reduction 5 0 0 0 90 180 270 360 450 540 630 720 0 180 360 540 720 Days 0 0 180 360 540 720 Days 900 *Time to sustained disability progression based on Kaplan-Meier method; based on Cox proportion hazards model, adjusted for treatment, region, baseline EDSS score, and age. HR=hazard ratio; NS=not significant. 1. Kappos L et al. N Engl J Med. 2010;362:387-401; 2. Agius M et al. Presented at CMSC, May 29 June 1, 2013, Orlando, FL. DX09. 4-5 Ιουνίου 2016 60
Reduction (%) Reduction (%) FREEDOMS: Ασθενείς με υψηλής δραστηριότητα της νόσου * Annualised Relapse Rate Reduction* Reduction in Risk of 12-Week (3-Month) Sustained EDSS Progression 100 100 80 60 55 % P<0.001 80 60 40 40 29 % P>0.500 20 20 0 Fingolimod vs Placebo (n=140) 0 Fingolimod vs Placebo (n=140) * 1 relapse in the previous year while on therapy and 9 T2-hyperintense or 1 Gd+ lesions OR a nonresponder (patient with unchanged or increased relapse rate or ongoing severe relapses) 2 disabling relapses in one year, and 1 GD+ lesions or significant increase in T2 lesion load. Gilenya (fingolimod [summary of product characteristics]. Horsham, West Sussex, UK: Novartis Europharm Ltd. 2011. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002202/human_med_001433.jsp&mid=wc0b01ac058001d 124. Accessed 3 March 2014. 4-5 Ιουνίου 2016 61
% of Patients Fingolimod: Freedom from Measured Disease Activity 60 Disease-free Patients at 2 Years 50 40 30 33 38 20 13 10 0 Placebo (n=418) Fingolimod 0.5mg (n=425) Fingolimod 1.25mg (n=429) Kappos L et al. Presented at AAN; April 9 16, 2011; Honolulu, Hawaii. PD6.002. 4-5 Ιουνίου 2016 62
Κίνδυνοι με τη χορήγηση Fingolimod Cardiovascular disease risk Macular edema Bradycardia AV block Teratogenic potential Lymphopenia and risk of infection Approximately 6 weeks for lymphocyte counts to return to LLN Use of attenuated live vaccines not possible prolonged treatment with corticosteroids! http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022527orig1s000riskr.pdf. Accessed April 24, 2012; Comi G et al. Mult Scler. 2010;16:197-207; Gilenya (fingolimod) [summary of product characteristics]. Horsham, West Sussex, UK: Novartis Europharm Ltd. 2011; Francis G et al. Presented at ECTRIMS, October 13-16 2010; Gothenburg, Sweden; P442; Karlsson G. Neurol. 2014;82:674-680. 4-5 Ιουνίου 2016 63
Lymphocyte Count ( 10 9 /L) Circulating Lymphocyte Count Markedly and Rapidly Decreased Change in Mean White Blood Cell Counts over Time in Patients Receiving Fingolimod Therapy or Placebo 2.8 (FREEDOMS Core Study Group) Fingolimod 0.5 mg (n=425) Fingolimod 1.25 mg (n=429) Placebo (n=418) 2.4 2.0 1.6 1.2 Rapid reduction in circulating lymphocytes >70% reduction in lymphocyte count within 7 days 1 Steady state levels reached within 2 weeks 2 0.8 Lower limit of normal 0.4 0 0 0.5 1 2 3 6 9 12 15 18 21 24 Time Point (months) Data are mean (standard deviation [SD]). In EU: Fingolimod is indicated for the treatment of patients with highly active RRMS. 1. Comi G et al. Mult Scler. 2010;16:197-207; 2. Francis G et al. Presented at ECTRIMS; October 13 16, 2010; Gothenburg, Sweden. P442. 4-5 Ιουνίου 2016 64
PANGAEA: Κίνδυνος υποτροπής στους πρώτους 6 μήνες μετά την αλλαγή θεραπείας από Natalizumab σε Fingolimod Relapse Activity Relapse Activity by Natalizumab Washout Period 22.2% Natalizumab Washout Period >180 days (n=104) >150 to 180 days (n=23) 18,3 17,7 77.8% >120 to 150 days (n=46) >90 to 120 days (n=114) >60 to 90 days (n=61) 17,6 20,5 23,5 No Relapses 1 Relapse 0 5 10 15 20 25 % of Patients PANGAEA: (Post-Authorization Non-interventional German safety study of GilEnyA). Prospective, multicenter, noninterventional German study of fingolimod in clinical practice 18-month interim analysis of 2239 fingolimod-treated patients, including 393 patients previously exposed to natalizumab No clear evidence that a shorter post-natalizumab washout period reduced risk of relapses during first 6 months of fingolimod treatment Ziemssen R et al. Presented at AAN; March 16 23, 2013; San Diego, CA. P01.185. 4-5 Ιουνίου 2016 65
MSBase: Αλλαγή θεραπείας από Natalizumab σε Fingolimod Natalizumab to fingolimod switch: Relapses during first 6 months of fingolimod use No relapses in 6 months prior to fingolimod treatment (n=44) 1 relapse in 6 months prior to fingolimod treatment (n=10) 11.0% 89.0% No relapses (% of patients) 1 relapse (% of patients) 30.0% 70.0% Jokubaitis et al. Presented at ECTRIMS; October 2 5, 2013; Copenhagen, Denmark. P179. 4-5 Ιουνίου 2016 66
4-5 Ιουνίου 2016 67
LESS EFFICACY MORE E Alemtuzumab Natalizumab JC Virus + Natalizumab JC Virus Third line? Second Line Fingolimod Dimethyl Fumarate First Line Teriflunomide Interferons Glatiramer Acetate LESS SAFETY MORE 4-5 Ιουνίου 2016 68
Alemtuzumab 4-5 Ιουνίου 2016 69
Alemtuzumab: Μηχανισμός Δράσης 1. Επιλεκτικά CD52 Monocytes 2. Εξάλειψη B 3. Επαναποικισμός Stem cell B CD52 Macrophages Neutrophils T T Pre/Pro B cell T-cell precursor CD52 CD52 Lymphocyte precursor Στοχεύει τα T και B κύτταρα που φέρονται ως υπεύθυνα για την φλεγμονώδη διεργασία στην ΠΣ 1 Μελέτες δείχνουν ότι τα κύτταρα της φυσικής ανοσίας που εκφράζουν χαμηλότερα επίπεδα CD52, επηρεάζονται ελάχιστα ή παροδικά από το alemtuzumab2 4-5 Ιουνίου 2016 Lymphocyte precursor Lymphocyte precursor Μειώνει την φλεγμονή της ΠΣ T B Μειώνει την δραστηριότητα της νόσου Το Alemtuzumab εξαλείφει επιλεκτικά τα κυκλοφορούντα T και B κύτταρα2,3 Τα προγονικά λεμφοκύτταρα μένουν ανέπαφα από το alemtuzumab2,4,5 Πολλά λεμφοκύτταρα παραμένουν στα λεμφικά όργανα μετά την θεραπεία 2,3 Ένα διακριτό πρότυπο επαναποικισμού των T- και Bκυττάρων ξεκινά μέσα σε λίγες εβδομάδες, που δυνητικά αλλάζει την ισορροπία του ανοσοποιητικού συστήματος2,4,5 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. 70
Το Πρόγραμμα Κλινικής Ανάπτυξης του Alemtuzumab: Συγκριτικές μελέτες έναντι SC IFNB-1a Φάση 2 Φάση 3 CAMMS223 (έχει ολοκληρωθεί) CARE-MS I (έχει ολοκληρωθεί) CARE-MS II (έχει ολοκληρωθεί) Extension/Επέκταση (βρίσκεται σε εξέλιξη) Ασθενείς, n 334 581 840 ~1400 Διάρκεια μελέτης, έτη Πληθυσμός ασθενών Θεραπευτικά σκέλη Συμπρωτεύοντα καταληκτικά σημεία 3 2 2 4 Ενεργή RRMS, Χωρίς προηγούμενη θεραπεία EDSS 3 Έναρξη νόσου 3 έτη Προσλαμβάνουσα βλάβη Alemtuzumab 12 mg Alemtuzumab 24 mg SC IFNB-1a 44 µg Ρυθμός Υποτροπής Εξέλιξη της Αναπηρίας Ενεργή RRMS, Χωρίς προηγούμενη θεραπεία EDSS 3 Έναρξη νόσου 5 έτη Alemtuzumab 12 mg SC IFNB-1a 44 µg Ρυθμός Υποτροπής Εξέλιξη της Αναπηρίας Ενεργή RRMS, Υποτροπή κατά την διάρκεια προηγούμενης θεραπείας EDSS 5 Έναρξη νόσου 10 έτη Alemtuzumab 12 mg Alemtuzumab 24 mg a SC IFNB-1a 44 µg Ρυθμός Υποτροπής Εξέλιξη της Αναπηρίας Ασθενείς από CAMMS223, CARE-MS I & II Alemtuzumab 12 mg 2 συνεδρίες (ασθενείς που πριν ήταν σε SC IFNB-1a) Επανάληψη αγωγής εάν χρειάζεται (ασθενείς που ήταν σε alemtuzumab) Ασφάλεια και Αποτελεσματικότητα a Διερευνητικό (exploratory) σκέλος, η στρατολόγηση διεκόπη νωρίς. SC IFNB-1a=subcutaneous interferon beta-1a, υποδόρια ιντερφερόνη βήτα-1α Rebif is a registered trademark of Merck Serono Europe Ltd. 1. Coles AJ et al. N Engl J Med 2008;359:1786-801; 2. Cohen JA et al. Lancet 2012;380:1819-28; 3. Coles AJ et al. Lancet 2012;380:1829-39; 4. Brinar V et al. ENS 2011, P912; 5. Fox E et al. AAN 2013, S41.001. 4-5 Ιουνίου 2016 71
Alemtuzumab Phase 3 Clinical Trials: Περίληψη αποτελεσματικότητας CARE-MS I (N=581) CARE-MS II (N=840) 55% vs SC IFNβ-1a Annualised 2 years 1,2 0.39 SC IFNβ-1a relapse rate at 0.18 alem vs P<0.0001 49% vs SC IFNβ-1a 0.26 alem vs 0.52 SC IFNβ-1a P<0.0001 Disability progression (6-month sustained) 1,2 30% vs SC IFNβ-1a 8% alem vs 11% SC IFNβ-1a P=0.22 42% vs SC IFNβ-1a 13% alem vs 20% SC IFNβ-1a P=0.0084 Disability improvement (6-month sustained) 3 Not assessed 157% vs SC IFNβ-1a 29% alem vs 13% SC IFNβ-1a P=0.0002 Patients MRI and clinically disease free 1,4 Odds ratio 1.75 39% alem vs 27% SC IFNβ-1a P=0.006 Odds ratio 3.03 32% alem vs 14% SC IFNβ-1a P<0.0001 1. Cohen JA et al. Lancet. 2012;380:1819-1828; 2. Coles AJ et al. Lancet. 2012;380:1829-1839; 3. Giovannoni G et al. Presented at AAN; March 16 23, 2013; San Diego, CA. P07.120; 4. Hartung HP et al. Presented at AAN; March 16 23, 2013; San Diego, CA. P07.093. 4-5 Ιουνίου 2016 72
Ασθενείς Χωρίς Προηγούμενη Θεραπεία Ελεύθεροι από Δραστηριότητα της Νόσου Percentage of Patients 1. Giovannoni G et al. ENS 2012. Platform; 2. Cohen JA et al. Lancet 2012;380:1819-28. Treatment-naïve: CARE-MS I 1,2 100 80 p<0.0001 SC IFNB-1a 44 µg Alemtuzumab 12 mg 60 40 56 74 42 p=0.0388 51 OR=1.75 p=0.0064 39 20 27 0 Clinical Disease Activity-free MRI Activity-free MS Disease Activity-free Στα 2 έτη, οι ασθενείς σε alemtuzumab είχαν >1.5 φορές μεγαλύτερη πιθανότητα να είναι ελεύθεροι από κάθε δραστηριότητα της νόσου συγκριτικά με τους ασθενείς σε SC IFNB-1a 1,2 4-5 Ιουνίου 2016 73
Συχνές παρενέργειες Event, % Infusion-associated reactions* Infection -Nasopharyngitis -UTI -Herpes infection -URTI Autoimmune -Thyroid disorder -Serious thyroid event -ITP SC IFNβ-1a (n=187) CARE-MS I 1 CARE-MS II 2 Alemtuzumab 12 mg/day (n=386) SC IFNβ-1a (n=202) Alemtuzumab 12 mg/day (n=426) Alemtuzumab 24 mg/day (n=170) NA 90 NA 90 97 45 13 4 2 13 6 0 0 67 20 17 16 15 18 1 1 66 24 11 4 12 5 0 0 77 29 21 16 16 16 <1 1 83 32 23 16 21 19 1 1 *Infusion associated reactions for the 12 mg/day dose included headache (43%), rash (39% 41%), pyrexia (16% 33%), nausea (14% 17%), urticaria (11% 15%), chills (7% 10%). Patients received acyclovir prophylaxis for herpes infections and were monitored for immune cytopenias and thyroid or renal disorders. NA=not applicable; UTI=urinary tract infection; URTI=upper respiratory tract infection; ITP=idiopathic thrombocytopenic purpura. 1. Cohen JA et al. Lancet. 2012;380:1819-1828; 2. Coles AJ et al. Lancet. 2012;380:1829-1839. 4-5 Ιουνίου 2016 74
Effects of Alemtuzumab in MS Persist at 5 Years After the initial two courses of treatment, 68% of treated patients from CARE-MS I and 60% of treated patients from CARE-MS II did not receive additional alemtuzumab during the following four years (ie, through month 60). The low annualized relapse rates observed in patients who received alemtuzumab in CARE-MS I (0.18) and CARE-MS II (0.27) were maintained from year three (0.19 and 0.22, respectively) to year five (0.15 and 0.18, respectively). Through year five, 80% and 76% of patients who received alemtuzumab in CARE-MS I and CARE- MS II, respectively, did not have worsening of disability progression confirmed over six months, as measured by the Expanded Disability Status Scale (EDSS). Through year five, 33% and 43% of patients who had disability before receiving alemtuzumab in CARE-MS I and CARE-MS II, respectively, had improvement in EDSS score confirmed over at least six months, as compared with pretreatment baseline. Through year five, patients who received alemtuzumab in CARE-MS I and II had a slowing of brain atrophy, as measured by brain parenchymal fraction on MRI. In each of years three, four, and five, most patients had no evidence of MRI disease activity (70 72% in CARE-MS I and 68 70% in CARE-MS II). Through year five, the incidence of most adverse events during the extension study was comparable to or lower than that of the pivotal studies. The frequency of thyroid adverse events was highest in year three and declined in the subsequent years. 4-5 Ιουνίου 2016 75 September 2015, ECTRIMS, Barcelona, Spain
Χειρισμός και παρακολούθηση αθενών σε Alemtuzumab During Treatment Counsel patients to Avoid live attenuated vaccines Report any adverse event, signs, or symptoms (especially fever, chills, swollen glands, bleeding gums, bruising, rashes) Use contraception Keep the Patient Alert Card with them and read Patient Guide Monitor (until 48 months after last infusion) Monthly CBC with differential Monthly renal function tests Serum creatinine levels Urinalysis with microscopy Quarterly thyroid function tests (TSH) Annual HPV screening for female patients Report adverse events by HCPs via the national reporting system TSH=thyroid-stimulating hormone; HPV=human papillomavirus; HCPs=healthcare professionals. Lemtrada (alemtuzumab) [summary of product characteristics]. Oxford, UK: Genzyme Therapeutics Ltd. 2013. http://www.ema.europa.eu/docs/en_gb/document_library/epar_-_product_information/human/003718/wc500150521.pdf. Accessed February 21, 2014. 4-5 Ιουνίου 2016 76
Χειρισμός και παρακολούθηση αθενών σε Alemtuzumab Treatment Discontinuation Alemtuzumab should be discontinued if severe infusion reactions occur After discontinuation, monitor for next 48 months CBC with differential at monthly intervals Monthly renal function tests Serum creatinine levels Urinalysis with microscopy Thyroid function tests (TSH) every 3 months Lemtrada (alemtuzumab) [summary of product characteristics]. Oxford, UK: Genzyme Therapeutics Ltd. 2013. http://www.ema.europa.eu/docs/en_gb/document_library/epar_-_product_information/human/003718/wc500150521.pdf. Accessed February 21, 2014. 4-5 Ιουνίου 2016 77
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Newer Drugs 4-5 Ιουνίου 2016 79
Am Health Drug Benefits. 2015;8(8):448-453 4-5 Ιουνίου 2016 80
Sphingosine 1-phosphate (S1P) is a soluble signaling molecule involved in a wide range of immunological, cardiovascular, and neurological processes through interaction with five members of a G-protein-coupled receptor family S1PR1, S1PR2, S1PR3, S1PR4, and S1PR5. Fingolimod is a sphingosine analogue that after phosphorylation functions as a modulator of S1PR1, S1PR3, S1PR4, and S1PR5. Interactions with S1PR1 and off -target interactions with other S1PR subtypes, particularly S1PR3, might mediate other potential adverse effects of fingolimod, including hypertension, macular oedema, pulmonary toxic effects, and hepatotoxicity Ozanimod is a novel, oral, selective, small-molecule S1PR1 and S1PR5 modulator. Ozanimod significantly reduced MRI lesion activity in participants with relapsing multiple sclerosis, with a favourable safety profile over a period of 24 weeks. These findings warrant phase 3 trials, which are ongoing. 4-5 Ιουνίου 2016 81
Ponesimod is an orally active, selective S1P1R modulator that causes dose-dependent sequestration of lymphocytes in lymphoid organs. In contrast to the long half-life/slow elimination of fingolimod, ponesimod is eliminated within 1 week of discontinuation and its pharmacological effects are rapidly reversible. Clinical data in multiple sclerosis have shown a dosedependent therapeutic effect of ponesimod and defined 20 mg as a daily dose with desired efficacy, and acceptable safety and tolerability. A gradual dose titration regimen was found to minimize the cardiac effects associated with initiation of ponesimod treatment. Selectivity for S1P1R, rapid onset and reversibility of pharmacological effects, and an optimized titration regimen differentiate ponesimod from fingolimod, and may lead to better safety and tolerability. Ponesimod is currently in phase III clinical development to assess efficacy and safety in relapsing multiple sclerosis. 4-5 Ιουνίου 2016 82
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FDA approves daclizumab to treat MS May 31, 2016 FDA approved on Friday daclizumab (Zinbryta; Biogen) for the treatment of adults with relapsing forms of multiple sclerosis (MS). The long-acting injectable drug is self-administered by the patient monthly. Among patients with relapsing remitting multiple sclerosis, daclizumab HYP showed efficacy superior to that of interferon beta-1a with regard to the annualized relapse rate and lesions, as assessed by means of MRI, but was not associated with a significantly lower risk of disability progression confirmed at 12 weeks. The rates of infection, rash, and abnormalities on liver-function testing were higher with daclizumab HYP than with interferon beta-1a 4-5 Ιουνίου 2016 85
PROGRESSIVE MS 4-5 Ιουνίου 2016 86
Glatiramer acetate in primary progressive multiple sclerosis: results of a multinational, multicenter, double-blind, placebo-controlled trial. Wolinsky JS1, Narayana PA, O'Connor P, Coyle PK, Ford C, Johnson K, Miller A, Pardo L, Kadosh S, Ladkani D; PROMiSe Trial Study Group. OBJECTIVE: To determine whether glatiramer acetate (GA) slows accumulation of disability in primary progressive multiple sclerosis. METHODS: A total of 943 patients with primary progressive multiple sclerosis were randomized to GA or placebo (PBO) in this 3-year, doubleblind trial. The primary end point was an intention-to-treat analysis of time to 1- (entry expanded disability status scale, 3.0-5.0) or 0.5-point expanded disability status scale change (entry expanded disability status scale, 5.5-6.5) sustained for 3 months. The trial was stopped after an interim analysis by an independent data safety monitoring board indicated no discernible treatment effect on the primary outcome. Intention-totreat analyses of disability and magnetic resonance imaging end points were performed. RESULTS: There was a nonsignificant delay in time to sustained accumulated disability in GA- versus PBO-treated patients (hazard ratio, 0.87 [95% confidence interval, 0.71-1.07]; p = 0.1753), with significant decreases in enhancing lesions in year 1 and smaller increases in T2 lesion volumes in years 2 and 3 versus PBO. Post hoc analysis showed that survival curves for GA-treated male patients diverged early from PBO-treated male subjects (hazard ratio, 0.71 [95% confidence interval, 0.53-0.95]; p = 0.0193). INTERPRETATION: The trial failed to demonstrate a treatment effect of GA on primary progressive multiple sclerosis. Both the unanticipated low event rate and premature discontinuation of study medication decreased the power to detect a treatment effect. Post hoc analysis suggests GA may have slowed clinical progression in male patients who showed more rapid progression when untreated. Ann Neurol. 2007 Jan;61(1):14-24. 4-5 Ιουνίου 2016 87
Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Hawker K1, O'Connor P, Freedman MS, Calabresi PA, Antel J, Simon J, Hauser S, Waubant E, Vollmer T, Panitch H, Zhang J, Chin P, Smith CH; OLYMPUS trial group. OBJECTIVE: Rituximab, a monoclonal antibody selectively depleting CD20+ B cells, has demonstrated efficacy in reducing disease activity in relapsing-remitting multiple sclerosis (MS). We evaluated rituximab in adults with primary progressive MS (PPMS) through 96 weeks and safety through 122 weeks. METHODS: Using 2:1 randomization, 439 PPMS patients received two 1,000 mg intravenous rituximab or placebo infusions every 24 weeks, through 96 weeks (4 courses). The primary endpoint was time to confirmed disease progression (CDP), a prespecified increase in Expanded Disability Status Scale sustained for 12 weeks. Secondary endpoints were change from baseline to week 96 in T2 lesion volume and total brain volume on magnetic resonance imaging scans. RESULTS: Differences in time to CDP between rituximab and placebo did not reach significance (96-week rates: 38.5% placebo, 30.2% rituximab; p = 0.14). From baseline to week 96, rituximab patients had less (p < 0.001) increase in T2 lesion volume; brain volume change was similar (p = 0.62) to placebo. Subgroup analysis showed time to CDP was delayed in rituximab-treated patients aged <51 years (hazard ratio [HR] = 0.52; p = 0.010), those with gadolinium-enhancing lesions (HR = 0.41; p = 0.007), and those aged <51 years with gadolinium-enhancing lesions (HR = 0.33; p = 0.009) compared with placebo. Adverse events were comparable between groups; 16.1% of rituximab and 13.6% of placebo patients reported serious events. Serious infections occurred in 4.5% of rituximab and <1.0% of placebo patients. Infusion-related events, predominantly mild to moderate, were more common with rituximab during the first course, and decreased to rates comparable to placebo on successive courses. INTERPRETATION: Although time to CDP between groups was not significant, overall subgroup analyses suggest selective B-cell depletion may affect disease progression in younger patients, particularly those with inflammatory lesions. 4-5 Ιουνίου 2016 Ann Neurol. 2009 Oct;66(4):460-71 88
Disappointing Results Announced from Clinical Trial of Tysabri (Natalizumab) in Secondary-Progressive MS October 21, 2015 Summary A phase III clinical trial of Tysabri (natalizumab, Biogen) compared with placebo in 889 people with secondary-progressive MS did not meet its primary endpoint, meaning that Tysabri was not shown to slow progression using a combined measure of disability. These results are reported in an October 21 press release from Biogen. Details of these results will be presented at a future medical meeting. 4-5 Ιουνίου 2016 89
970 patients were randomly assigned between Sept 3, 2008, and Aug 30, 2011 (147 to fingolimod 1 25 mg and 133 to placebo in cohort 1; 336 to fingolimod 0 5 mg and 354 to placebo in cohort 2). The effi cacy analysis set (n=823) consisted of 336 patients randomly allocated to fingolimod 0 5 mg and 487 to placebo Interpretation The anti-inflammatory effects of fingolimod did not slow disease progression in primary progressive multiple sclerosis. Therapeutic strategies for primary progressive multiple sclerosis might need diferent approaches to those used for relapse-onset multiple sclerosis. 4-5 Ιουνίου 2016 90
OCRELIZUMAB 4-5 Ιουνίου 2016 91 Autoimmun Rev (2016), http://dx.doi.org/10.1016/,j.autrev.2016.03.006
OCRELIZUMAB 4-5 Ιουνίου 2016 92
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The investigational drug ocrelizumab significantly reduces progression of clinical disability compared with placebo in patients with primary progressive multiple sclerosis (PPMS), topline results of a pivotal phase 3 study (ORATORIO) released by Roche show. ORATORIO, a randomized, double-blind, multicenter study evaluated the efficacy and safety of ocrelizumab (600 mg administered by intravenous infusion every 6 months; given as two 300-mg infusions 2 weeks apart) compared with placebo in 732 patients with PPMS. Its primary endpoint, which was met, was time to onset of confirmed disability progression, defined as an increase in Expanded Disability Status Scale (EDSS) that is sustained for at least 12 weeks. Ocrelizumab is the first investigational medicine to show a clinically meaningful and statistically significant effect on the progression of disease in primary progressive MS. 4-5 Ιουνίου 2016 94 September 2015, ECTRIMS, Barcelona, Spain
Basel, 17 February 2016 U.S. FDA grants Breakthrough Therapy Designation for Roche s investigational medicine ocrelizumab in primary progressive multiple sclerosis Ocrelizumab is the first investigational medicine to receive Breakthrough Therapy Designation in multiple sclerosis (MS) Twelfth Breakthrough Therapy Designation for Roche s portfolio of medicines since 2013 Roche (SIX: RO, ROG; OTCQX: RHHBY) announced today that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation for the investigational medicine ocrelizumab (OCREVUS TM ) for the treatment of people with primary progressive multiple sclerosis (PPMS). There are currently no approved treatments for PPMS, a debilitating form of MS characterised by steadily worsening symptoms and typically without distinct relapses or periods of remission. 4-5 Ιουνίου 2016 95
Βιοτίνη- Βιταμίνη Β7 4-5 Ιουνίου 2016 96
Washington, DC (April 30, 2015) A regimen of high doses of biotin, a water-soluble B vitamin, appears to be effective in patients with primary or secondary progressive multiple sclerosis (MS), according to emerging research. A new phase 3 study of the investigational drug MD1003 (MedDay Pharmaceuticals), a highly concentrated pharmaceutical-grade biotin, found that patients with progressive MS taking the drug had significant improvement at 9 months, which was confirmed at 12 months, compared with those taking placebo. Biotin is a coenzyme for carboxylases, which are enzymes critical in energy metabolism and production of fatty acids. It targets two mechanisms that might be involved in progressive MS: promoting myelination and increasing energy production. It's hypothesized that biotin may help to slow, stop, or even reverse the progression of disability associated with demyelination. The new study included 154 patients aged 18 to 75 years (mean age, about 51 years) with primary or secondary progressive MS and an EDSS score of 4.5 to 7. During the previous 2 years, they must have had a progression on the EDSS of at least 1 point if their baseline EDSS score was 4.5 to 5.5, and of 0.5 point if their baseline EDSS score was 6 to 7. The main outcome was improvement at 9 months, and confirmed at 12 months, using either a change in EDSS score of at least 1 point (if baseline EDSS was 4.5 to 5.5) and 0.5 point (if baseline EDSS was 6 to 7) or a decrease in timed 25-foot walk (TW25) of 20% compared to baseline. In the ITT population, 12.62% of the MD1003 group and 0.0% of the placebo group met this criteria (P =.0051). In the per protocol population, 14.9% of the MD1003 and 0.0% of the placebo group met the primary endpoint (P =.0093). Pregnant women or those who are planning to become pregnant should not take these very high doses of this vitamin! 4-5 Ιουνίου 2016 97 (AAN) 67th Annual Meeting. Clinical Trials Plenary Session. Presented April 24, 2015.
Επαναμυελίνωση 4-5 Ιουνίου 2016 98
Anti-LINGO-1 4-5 Ιουνίου 2016 99
We assessed cognitive function at early and late stages of EAE, determined brain expression of myelin basic protein (MBP) and investigated whether the LINGO-1 antibody could restore deficits in learning and memory and ameliorate any loss of MBP. We found that deficits in learning and memory occurred in late EAE and identified decreased expression of MBP in the parahippocampal cortex (PHC) and fimbria-fornix. Moreover, the LINGO-1 antibody significantly improved learning and memory in EAE and partially restored MBP in PHC. Furthermore, the LINGO-1 antibody activated the AKT/mTOR signaling pathway regulating myelin growth. Our research demonstrates that LINGO-1 antagonism may be an effective approach to the treatment of the cognitive impairment of multiple sclerosis patients. 4-5 Ιουνίου 2016 100
Biogen Idec Reports Positive Top-Line Results from Phase 2 Anti-LINGO-1 Trial in People with Acute Optic Neuritis SHARE Biogen Idec Reports Positive Top-Line Results from Phase 2 Anti-LINGO-1 Trial in People with Acute Optic Neuritis - Data Offer Evidence of Proof of Biology in Acute Optic Neuritis - - Phase 2 Multiple Sclerosis Trial Ongoing, Data Expected in 2016 Will Further Define Clinical Potential - 4-5 Ιουνίου 2016 101
Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo Oligodendrocyte progenitor cells are stem cells in the central nervous system and the principal source of myelinating oligodendrocytes. These cells are abundant in demyelinated regions of patients with multiple sclerosis, yet fail to differentiate, thereby representing a cellular target for pharmacological intervention. Two drugs, miconazole and clobetasol, are effective in promoting precocious myelination in organotypic cerebellar slice cultures, and in vivo in early postnatal mouse pups. Systemic delivery of each of the two drugs significantly increases the number of new oligodendrocytes and enhances remyelination in a lysolecithin-induced mouse model of focal demyelination. Immune response assays show that: 1). miconazole functions directly as a remyelinating drug with no effect on the immune system, whereas clobetasol is a potent immunosuppressant as well as a remyelinating agent. Mechanistic studies show that 2.) miconazole and clobetasol function in oligodendrocyte progenitor cells through mitogen-activated protein kinase and glucocorticoid receptor signalling, respectively. Furthermore, 3.) both drugs enhance the generation of human oligodendrocytes from human oligodendrocyte progenitor cells in vitro. 4-5 Ιουνίου 2016 102 Nature, Published online 20 April 2015
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Διάφορα- Άλλα 4-5 Ιουνίου 2016 104
Clinical Dilemmas in Treating MS- Vitamin D Literature Search Methods Canadian Agency for Drugs and Technologies in Health A limited literature search was conducted on key resources including PubMed, The Cochrane Library, University of York Centre for Reviews and Dissemination (CRD) databases, Canadian and major international health technology agencies, as well as a focused Internet search. No filters were applied to limit the retrieval by study type. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2011 and February 9, 2016. For prevention, limited evidence from one NRS (Non Randomized Clinical Trial)and one RCT (Randomized Clinical Trial) suggests potential benefits of cod liver oil supplementation during adolescence on MS riskas well as a reduced risk of second demyelinating attacks and lower occurrence of various lesions as visualized by MRI,with no apparent risks of supplementation in patients with optic neuritis. For treatment with vitamin D versus no vitamin D, there was no evidence to suggest a benefit for disease activity. For treatment with high dose vitamin D versus low dose vitamin D, evidence presented from one trial reported higher relapse rates in high dose patients, while evidence from another trial suggested no difference in the odds of relapse, and finally another trial suggested no differences in relapse rates between groups. Current guidelines from the National Institute for Health and Care Excellence on the management of MS in adults state that vitamin D should not be offered solely for the purpose of treating MS. However, MS patients should maintain sufficient intake of 4-5 Ιουνίου 2016 105 vitamin D to ensure adequate vitamin D status.
Prevalence of extracranial venous narrowing on catheter venography in people with multiple sclerosis, their siblings, and unrelated healthy controls: a blinded, case-control study Chronic cerebrospinal venous insufficiency has been proposed as a unique combination of extracranial venous blockages and haemodynamic flow abnormalities that occurs only in patients with multiple sclerosis and not in healthy people. This study shows that chronic cerebrospinal venous insufficiency occurs rarely in both patients with multiple sclerosis and in healthy people. Extracranial venous narrowing of greater than 50% is a frequent finding in patients with multiple sclerosis, unaffected siblings, and unrelated controls. The ultrasound criteria are neither sensitive nor specific for narrowing on catheter venography. The significance of venous narrowing to multiple sclerosis symptomatology remains unknown. 4-5 Ιουνίου 2016 106 Lancet, Volume 383, No. 9912, p138 145, 11 January 2014
Trial Method Patients Type Results Complications Shevchenko et al. 2015 Auto-HSCT in with high-dose immunosuppressive therapy All MS types Ongoing NA (HDIT),with a decreased intensity BEAM condition regimen Fassas A et al, 2000 Auto-HSCT with BEAM (BCNU 99 patients; 43 RR-MS, 35 SP-MS, 18 No transplanted deaths observed and the cumulative No deaths BEAM (BCNU(carmustine), cytarabine, etoposide, melphalan) PPMS, incidence of disease progression was 16.7 % at 8 years and three PR-MS post-transplantation. These studies were very favorable because 47% of the patients improved in their EDSS score (at least 0.5), as compared with the baseline, and 45 % of MS patients were stable at median long-term follow-up Fassas A et al, 2011 Saccardi R et al, 2006 Auto- hematopoietic stem cells transplantation (HSCT) 183 multiple sclerosis (MS) patients, from database of the European Blood and Marrow Transplantation Group (EBMT). Faguis et al, 2009 Auto-HSCT with BEAM (BCNU BEAM (BCNU(carmustine), cytarabine, etoposide, melphalan) Auto-HSCT with BEAM condition followed auto-hsct with BEAM condition followed by cyclophosphamide for more than 5 years in both the RR-MS and 35 patients with progressive MS sustained and impressive effect in suppressing disease activity after a medium follow-up period of 11 (range 2 15) years. At 15 years,disease (progression-free) survival was 44 % for patients with active CNS disease and 10 % for those without. There was an improvement in EDSS scores in 16 patients by 0.5 5.5 for a median of 2 years Improvement or stabilization of neurological conditions occurred in 63% of patients at a median follow-up of 41.7 months Nine patients with malignant RR-MS One relapse in 280 patient-months following HSCT. All patients had their disability improve or stabilize, and most of the patients showed no enhanced lesions during follow-up. Transplant related mortality (TRM) was 5.3% 4-5 Ιουνίου 2016 107 Two deaths NO