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1. Disease Modifying
Treatments:
Mediocrity and then some?
Dr Trevor Pickersgill
Consultant Neurologist
University Hospital of Wales
Royal Glamorgan Hospital
Hon Lecturer, Cardiff University
22. The IFNB Multiple Sclerosis Study
Group. 1993 Neurology. 43: 655-
661
Jacobs LD et al. 1996 Annals of
Neurology. 39: 285-294
The PRISMS Study Group. 1998
Lancet. 352: 1498-1504
Jacobs LD et al. 2000 New
England Journal of Med
Medicine. 343: 898-904
European Study Group on
Interferon-1b in Secondary
Progressive MS. 1998 Lancet.
352: 1491-1497
Comi G et al. 2001 Lancet. 357:
1576-1582
30. Natalizumab/Tysabri
Monthly IVI, £13K
+MRI +monthly day case = c.£18k
‘twice’ as effective injectable DMT
Reserved for ‘HARRMS’ (NICE)
I.e. 2+attacks in 1 yr with active MRI
(significant increase in lesions or Gd+)
25+ UHW.
PML......
31. MOA of Natalizumab
1. Leukocyte migration
from blood to tissue
2. Leukocyte priming
and activation
3. Modulation of
leukocyte apoptosis
Cannella B et al. Ann Neurol. 1995;37:424-435.
TYSABRI SmPC; Yednock TA et al. Nature.
1992;356:63-66
32. TYSABRI Efficacy Summary
ITT Population
68% reduction in relapse rate vs placebo
over 2 years (p < 0.001)
54%
reduction in the risk of EDSS
progression, sustained for 24 weeks, as
assessed over 2 years (p < 0.001)
of patients free from all of the following
28%
measures of disease activity: relapses, Gd+
lesions, T1 weighted hypointense and T2
weighted hyperintense lesions and disability
progression at 2 years 2
TYSABRI SmPC; Polman CH, et al. NEJM 2006; 354(9):
899-910; 2. TY00-004, Data on file. Biogen Idec Ltd
33.
34. Kaplan–Meier Plots of the Time to Sustained Progression of Disability among
Patients Receiving Natalizumab, as Compared with Placebo.
29%
-42%
17%
Polman CH et al. N Engl J Med 2006;354:899-910.
35. The downside...PML
1 in 1000...? Think again........
Untreatable brain virus
Competent immune system - asymptomatic
Est 30-50% prevalence
45. Cumulative number of relapses over time
Risk
Reduction
87% 72%
P <0.0001
Annualized Relapse Rate (95% C.I.)
Interferon-beta 1a Alemtuzumab Low- Alemtuzumab High-
0.35 (0.27, 0.44) Dose Dose
0.11 (0.07, 0.16) 0.05 (0.03, 0.09)
Coles et al. AAN 2007.
46. Mean EDSS Score Over Time
Alemtuzumab
v. IFNB1a
-0.57 (-0.30, -0.83)
-0.72 (-0.46, -0.98)
P<0.0001
Error bars = S.E.
56. CLADRIBINE
The ‘winner’ of the race to market
CLARITY NEJM 2010
N=1326
Placebo v high v low dose
0.33 v 0.15 relapse rate
10 tumours (5 fibroids!)
Withdrawn from market worldwide
57. Efficacy Outcome Measures Relating to Relapse and Progression of Disability during
the 96-Week Study Period (Intention-to-Treat Population).
Giovannoni G et al. N Engl J Med 2010;362:416-426.
59. FINGOLIMOD
S1P receptor modulator
TRANSFORMS v Avonex
FREEDOMS v placebo
EDSS 0-5.5 ARR=1
N=1200 82% completion
-54% RR
MRI and disability
Oral once daily
Isaria sinclarii
60. FINGOLIMOD
First dose in hospital
Cardiac SEs
First dose brady
1/2 deg HB
Opthalmological - mac oedema
Skin - 11 cancers (4 pl)
£20,000
61. Gilenya prevents lymphocyte exit
from lymph nodes
Gilenya causes:
Internalisation of
the S1P1 receptor
Inhibition of
lymphocyte exit
along the S1P
gradient
Gilenya induces reversible retention of circulating lymphocytes in lymph nodes, reducing
peripheral lymphocyte counts and their recirculation to the CNS
CNS, central nervous system; S1P, sphingosine 1-phosphate
Model based on Brinkmann V et al. J Biol Chem 2002; Matloubian M et al. Nature 2004; Brinkmann V. Br J Pharmacol 2009
62. Annualized Relapse Rate at 12 Months and the Time to the First Relapse.
Cohen JA et al. N Engl J Med 2010;362:402-415.
63. Fingolimod significantly reduced annualized
relapse rates versus IFNβ-1a IM and placebo
TRANSFORMS 1-year results11 FREEDOMS 2-year results22
FREEDOMS 2-year results
TRANSFORMS 1-year results
p < 0.001 for fingolimod versus IFNβ-1a IM p < 0.001 for fingolimod versus placebo
0.4
0.4
0.3
0.3 0.40
Annualized relapse rate
Annualized relapse rate
0.33 0.17 or 52% 0.22 or 54%
0.2
reduction 0.2 reduction
0.1
0.1
0.18
0.16
0
0
IFNβ-1a IM Fingolimod 0.5 mg Placebo Fingolimod 0.5 mg
(n = 431) (n = 429) (n = 418) (n = 425)
Annualized Relapse Rate estimate and p value are calculated using negative binomial regression model adjusted
for treatment group, country, number of relapses in previous 2 years and baseline EDSS score.
EDSS, Expanded Disability Status Scale; IM, intramuscular 1. Table 2 page 8 FDA Advisory Committee presentation (10 June 2010).
2. Cohen JA et al. N Engl J Med 2010;362:402–15.
Data refers to study group broader than the CHMP licensed indication. Fingolimod is indicated in patients with highly active and rapidly evolving severe
RRMS. A consistent treatment effect was demonstrated in the licensed highly active subgroups.”
64. Fingolimod reduced ARR in patients with
highly active RRMS despite prior DMT, at
1 year (TRANSFORMS)
Subgroups relevant to the approved EU label
Patients with highly active Patients with highly active Overall TRANSFORMS
disease despite prior IFNβ disease despite prior IFNβ population***
(relapse and MRI criteria)* (relapse criteria only)**
0.8 -0.31 or -61% 0.8 -0.31 or -61% 0.8 -0.22 or -52%
vs. IFNβ-1a IM vs. IFNβ-1a IM vs. IFNβ-1a IM
0.6 p<0.001 0.6 p<0.001 0.6 p<0.001
0.51 0.51
ARR
ARR
ARR
0.4 0.4 0.4 0.43
0.2 0.2 0.2
0.20 0.20 0.21
0 0 0
n = 149 n = 160 n = 138 n = 166 n = 431 n = 429
IFNβ-1a IM Fingolimod 0.5 mg
*IFN and ≥1 relapse in the year prior to study, plus either ≥1 Gd-enhancing lesions or ≥9 T2 lesions at
baseline;**IFN in the year prior to study, plus equal or more relapses in Year -1 than in Year -2; based on
relapse rate ratio; ***Aggregate ARR is presented.
Cohen J et al. ENS 2011; poster P901
FIN12-C117
Date of preparation September 2012
66. Annualized Relapse Rate and
Sustained Disability
Progression.
TEMSO
O'Connor P et al. N Engl J Med
2011;365:1293-1303.
67. TOWER
2nd phase 3 trial terif
Alopecia 13%
1+relapse 1yr 2+ 2yrs
TENERE: no superiority
Rebif
48wks n=1169
TOPIC - CIS
70% completed study
ARR -22.3% -36.3%
Effective, well tolerated,
Free relapses 55.4% v
more long term safety data
37.7%
needed
SAD 22/21% v 15.8% 2M pt-yrs in RA
68.
69.
70.
71. BG12/DMF
Anti inflamm antioxidative stress
?cytoprotective
DEFINE v pl /CONFIRM v pl v GLA
Fox NEJM 2012
50% RR
SAD 33%
72. BG-12/DMF
Risk relapse 2yrs 43%
New/enlarging T2 75%
N=2307 120 v 240 v pl v GLA (n=360)
At least 1 relapse 12m
-83% Gd+
Flushing/GI SEs
73. Clinical Outcomes at 2
Years in the Intention-to-
Treat Population.
Fox RJ et al. N Engl J Med
2012;367:1087-1097.
74. LAQUNIMOD
ALLEGRO 23% RR 36% SAD
BRAVO
More
pronounced effect on disability than
RR??
75. Clinical Outcomes and MRI Measures
of Efficacy According to Study
Group.
ALLEGRO
Comi G et al. N Engl J Med
2012;366:1000-1009.
76.
77.
78.
79. Treatment Map
CIS RRMS HARRMS
NEW
ABCR ORALS
NAT
Monoclonals
FING
Adapted from X Montalban ECTRIMS 2012 ALEM
80. Acknowledgements
Slideshare - Prof G Giovannoni
Helen Durham Centre:
Dr Katharine Harding
Dr Mark Cossburn
Prof Neil Robertson
Dr Sebastian Luppe
Dr Claire Hurst
Editor's Notes
The current theoretical model regarding effects of treatment postulates that the early intervention at the time of diagnosis is likely to result in slower accumulation of disability, compared to disability accumulation in patients who receive treatment later in the course of disease or in patients who do not receive treatment at all.
Patients with a sustained (6 months) Expanded Disability Status Scale increase during the first 3 years of treatment. In the Forest plot, each trial is represented by a square, with the centre denoting the RR for that trial and the extremities of the horizontal bars denoting 95% CI. Square size is directly proportional to the weight of the trial within the group of trials. The diamond gives the overall RR for all trials: its centre denotes the RR and extremities the 95% CI. Trials are ordered chronologically. Risk ratios were estimated by the Mantel–Haenszel approach using a random effects model. *Data extracted from Kappos 2001.23 n=number of patients with outcome; N=number of randomised patients.
References: 1. Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol 1996;39:285–94. (reprint available)
NAT-LIZ-MAB: Queen Mab Romeo and Juliet Mercutio’s speech: "O, then, I see Queen Mab hath been with you. She is the fairies � midwife, and she comes In shape no bigger than an agate-stone On the fore-finger of an alderman, Drawn with a team of little atomies Athwart men's noses as they lie asleep; Her wagon-spokes made of long spinners � legs, The cover of the wings of grasshoppers,...”
TIE-SAAB-RI
von Andrian UH, Engelhardt B. 4 integrins as therapeutic targets in autoimmune disease. N Engl J Med. 2003;348:68-72. TYSABRI (natalizumab) Prescribing Information, 2004. Yednock TA, Cannon C, Fritz LC, Sanchez-Madrid F, Steinman L, Karin N. Prevention of experimental autoimmune encephalomyelitis by antibodies against 4 ß1 integrin. Nature . 1992;356:63-66.
Figure 2. Kaplan–Meier Plots of the Time to Sustained Progression of Disability among Patients Receiving Natalizumab, as Compared with Placebo. Natalizumab reduced the risk of sustained progression of disability by 42 percent over two years (hazard ratio, 0.58; 95 percent confidence interval, 0.43 to 0.77). The cumulative probability of progression was 17 percent in the natalizumab group and 29 percent in the placebo group.
AL-EMINEM-TOOTSIE-MAB
CAMP-PATH
The acute haematological effects of C1H infusion of C1H over 4 hours reduction inlymphocytes is rapid neutrophils go up effect of steroids
OCRE-LIZ-OONA-MAB
Figure 1. Efficacy Outcome Measures Relating to Relapse and Progression of Disability during the 96-Week Study Period (Intention-to-Treat Population). Shown are the annualized rates of relapse (Panel A), Kaplan–Meier curves of the time to the first relapse (Panel B), the cumulative number of relapses over time (Panel C), and Kaplan–Meier curves of the time to 3-month sustained progression of disability, according to scores on the Expanded Disability Status Scale (EDSS) (Panel D). In Panel A, the T bars represent 95% confidence intervals. P values that are shown in Panels B and D are for hazard ratios and 95% confidence intervals during the 96-week period, as estimated with the use of a Cox proportional-hazards model with fixed effects for study group and region.
GILL-ENYA
Isaria sinclarii: Isaria sinclairii is a fungus which attacks insects , including cicada larvae . The larvae typically die just beneath the soil surface, and the fungus produces white tufts which grow up from the soil and release powdery white spores . [2] [ edit ]Uses Myriocin (2-amino-3,4-dihydroxy-2-(hydroxymethyl)-14-oxoicos-6-enoic acid) is a sphingolipid derivative produced by I. sinclairii , which was shown in 1994 to have immunosuppressive properties . [3] [4] A synthetic derivative was developed to have greater effectiveness lower toxicity and named FTY720, or fingolimod . [3] [5] This is the first oral disease-modifying drug for multiple sclerosis . [3]
Downregulation of S1P receptors is an aspect of the normal immune process which is why the effects of Gilenya preserve normal lymphocyte function 1 Gilenya restricts immune cell entry into the CNS by retaining T and B lymphocytes in secondary lymphoid tissues 2 The majority of circulating lymphocytes are thus retained in lymph nodes, reducing peripheral lymphocyte counts and the recirculation of lymphocytes to the CNS 1. Chun J and Hartung HP. Clin Neuropharmacol 2010 2. Kappos L, Antel J, Comi G, et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med. 2006;355:1124-1140.
Figure 2. Annualized Relapse Rate at 12 Months and the Time to the First Relapse. Panel A shows the annualized rate of relapse from baseline to 12 months, with adjustment for study group, country, number of relapses in the previous 2 years, and baseline disability score. Panel B shows Kaplan–Meier estimates of the time to the first relapse, indicating the proportion of relapse-free patients (P<0.001 for both comparisons with interferon).
Figure 2. Annualized Relapse Rate and Sustained Disability Progression. The adjusted annualized relapse rate (Panel A) was derived from an analysis of the number of relapses with the use of a Poisson regression model adjusted for treatment and score on the Expanded Disability Status Scale at baseline and geographic region, with the log of time during treatment serving as an offset variable. The relative reductions versus placebo were calculated according to numbers before rounding. I bars represent 95% confidence intervals. Panel B shows progression of disability that was sustained for at least 12 weeks.
BEE-GEE 12
Figure 1. Clinical Outcomes at 2 Years in the Intention-to-Treat Population. Annualized relapse rates (Panel A) were calculated with the use of a negative binomial regression model, with adjustment for baseline score (less than or equal to 2.0 vs. >2.0) on the Expanded Disability Status Scale (EDDS, which ranges from 0 to 10, with higher scores indicating a greater degree of disability), baseline age (<40 years vs. greater than or equal to 40 years), region (regions were defined on the basis of not only geography but also the type of health care system and access to health care in each country), and number of relapses in the 12 months before study entry. Relapses were confirmed by an independent neurologic evaluation committee. The I bars indicate 95% confidence intervals. Hazard ratios for time to disability progression (Panel B) were calculated with the use of a Cox proportional-hazards model, with adjustment for baseline EDSS score, baseline age (<40 years vs. greater than or equal to 40 years), and region. The estimated proportions of patients with disability progression at 2 years are Kaplan–Meier estimates.
Figure 1. Clinical Outcomes and MRI Measures of Efficacy According to Study Group. Panel A shows the number of confirmed relapses. Panel B shows the Kaplan–Meier plot for the risk of disability progression that was confirmed after 3 months, as measured by scores on the Expanded Disability Status Scale. Panel C shows the adjusted mean number of gadolinium-enhancing lesions at baseline, at 12 months, and at 24 months and the cumulative number at 24 months. T bars indicate standard errors.