dmt m strust_nov12_final
DESCRIPTION
Keynote given to UK MS Trust annual conference 5th November 2011, Kenilworth, Coventry, UK.TRANSCRIPT
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Disease Modifying Treatments:
Mediocrity and then some?
Dr Trevor Pickersgill
Consultant Neurologist
University Hospital of Wales
Royal Glamorgan Hospital
Hon Lecturer, Cardiff University
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Declarations
Research post 1996-8 - Schering AG ESPMS trial Travel/Conference hospitality: Biogen-Idec, Merck-Serono,
Novartis Advisory Board Remuneration: Biogen-Idec, Teva Educational Grants: GSK, Teva, UCB Minor shareholder: GSK; ex-Genzyme Directorships: BMA, BMA Pension Trustees Ltd.
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“Disease?”
Advice Explanation Expertise Support Signposting Now ‘rationers’ ‘prescribers’
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“Modifying”
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Theoretical model: treat early and aggressively
Treatmentat diagnosis Intervention
at diagnosis
Time
Disease Onset
Dis
abili
ty
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Patients with a sustained (6 months) Expanded Disability Status Scale increase during the first 3 years of treatment.
La Mantia L et al. J Neurol Neurosurg Psychiatry doi:10.1136/jnnp-2012-303291
©2012 by BMJ Publishing Group Ltd
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RM dob 1987….inflammation in 2005
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….atrophy 2012….
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“Treatment?”
K Harding et al ENS 2012
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‘mild’ drugs?
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The Pipeline
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Teva/Serono
BIOGEN
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Really…..?
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The IFNB Multiple Sclerosis Study The IFNB Multiple Sclerosis Study Group. 1993 Neurology. 43: 655-Group. 1993 Neurology. 43: 655-661661Jacobs LD et al. 1996 Annals of Jacobs LD et al. 1996 Annals of Neurology. 39: 285-294Neurology. 39: 285-294The PRISMS Study Group. 1998 The PRISMS Study Group. 1998 Lancet. 352: 1498-1504Lancet. 352: 1498-1504Jacobs LD et al. 2000 New Jacobs LD et al. 2000 New England Journal of Med England Journal of Med Medicine. 343: 898-904Medicine. 343: 898-904European Study Group on European Study Group on Interferon-1b in Secondary Interferon-1b in Secondary Progressive MS. 1998 Lancet. Progressive MS. 1998 Lancet. 352: 1491-1497352: 1491-1497Comi G et al. 2001 Lancet. 357: Comi G et al. 2001 Lancet. 357: 1576-15821576-1582
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The New Dawn:monoclonals
Alemtuzumab Natalizumab Daclizumab Ocrelizumab Rituximab
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“I’ll name that DMT in......”
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AKA.......
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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......
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MOA of Natalizumab
1. Leukocyte migration from blood to tissue
3. Modulation of leukocyte apoptosis
2. Leukocyte priming and activation
Cannella B et al. Ann Neurol. 1995;37:424-435. TYSABRI SmPC; Yednock TA et al. Nature. 1992;356:63-66
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TYSABRI Efficacy Summary
68%
54%
reduction in relapse rate vs placebo over 2 years (p < 0.001)
reduction in the risk of EDSS progression, sustained for 24 weeks, as assessed over 2 years (p < 0.001)
28%of patients free from all of the following 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
ITT Population
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Kaplan–Meier Plots of the Time to Sustained Progression of Disability among Patients Receiving Natalizumab, as Compared with Placebo.
Polman CH et al. N Engl J Med 2006;354:899-910.
29%
17%
-42%
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The downside...PML
1 in 1000...? Think again........ Untreatable brain virus Competent immune system - asymptomatic Est 30-50% prevalence
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Q’aeda
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Another magic bullet?
Alemtuzumab Anti CD52 Cell lysis Lymphocyte depleter Annual infusions x2 Cheap..... .....but withdrawn autoimmunity
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AKA......
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0
0.5
1
1.5
2
2.5
0 4 8 12 16 20 24
Haematological Effects of CAMPATH-1H
Time post Campath Infusion (Hours) 95% reduction within 1hr. Unaffected by steroids
Lym
ph
ocy
tes
(x10
9 /l)
0
1
2
3
4
1 10 100 1000
Days post CAMPATH-1HL
ymp
ho
cyte
s (x
109 /
l)
Normal Range
Moreau, T., A. Coles, et al. (1996). Moreau, T., A. Coles, et al. (1996). BrainBrain 119 (Pt 1)119 (Pt 1): 225-37: 225-37
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Lymphocyte recovery after Alemtuzumab
Cossburn et al Neurology 2012(in press)
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Campath rash
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Cumulative number of relapses over time
P <0.0001
72%87%
RiskReduction
Annualized Relapse Rate (95% C.I.)
Interferon-beta 1a0.35 (0.27, 0.44)
Alemtuzumab Low-Dose
0.11 (0.07, 0.16)
Alemtuzumab High-Dose
0.05 (0.03, 0.09)Coles et al. AAN 2007.
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Mean EDSS Score Over Time
-0.57 (-0.30, -0.83)
-0.72 (-0.46, -0.98) P<0.0001
Alemtuzumabv. IFNB1a
Error bars = S.E.
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CARE-MS I/II
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The downside......
30% thyroid
3% ITP
Goodpasture’s
Lymphoma
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The newest downside....
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Ocrelizumab ‘ritux-max’ CD20 Phase 2 n=220 6 monthly infusion MRI
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Others
Rituximab 1 small trial
Daclizumab IL2recA chain CD25
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The Oral Explosion....
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Fingolimod
BG12/DMF
Teriflunomide “Aubagio”
Laquinimod
Cladribine
Ponesimod ??
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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
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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.
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Name that (oral) DMT....
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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
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FINGOLIMOD
First dose in hospital Cardiac SEs First dose brady 1/2 deg HB Opthalmological - mac oedema Skin - 11 cancers (4 pl) £20,000
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Gilenya prevents lymphocyte exit from lymph nodes
Gilenya causes: Internalisation of
the S1P1 receptor Inhibition of
lymphocyte exit along the S1P gradient
CNS, central nervous system; S1P, sphingosine 1-phosphateModel based on Brinkmann V et al. J Biol Chem 2002; Matloubian M et al. Nature 2004; Brinkmann V. Br J Pharmacol 2009
Gilenya induces reversible retention of circulating lymphocytes in lymph nodes, reducing peripheral lymphocyte counts and their recirculation to the CNS
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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.
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0
0.1
0.2
0.3
0.4
Fingolimod significantly reduced annualized relapse rates versus IFNβ-1a IM and placebo
0
0.1
0.2
0.3
0.4
TRANSFORMS 1-year results1TRANSFORMS 1-year results1 FREEDOMS 2-year results2FREEDOMS 2-year results2
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.
p < 0.001 for fingolimod versus IFNβ-1a IM p < 0.001 for fingolimod versus placebo
IFNβ-1a IM(n = 431)
Fingolimod 0.5 mg(n = 429)
Placebo(n = 418)
Fingolimod 0.5 mg(n = 425)
0.33
0.16
0.40
0.18
Ann
ualiz
ed r
elap
se r
ate
Ann
ualiz
ed r
elap
se r
ate
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.
0.17 or 52% reduction
0.22 or 54% reduction
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.”
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Fingolimod reduced ARR in patients with highly active RRMS despite prior DMT, at 1 year (TRANSFORMS)
*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
Patients with highly active disease despite prior IFNβ
(relapse criteria only)**
0.51
0.20
0
0.2
0.4
0.6
0.8
0.51
0.20
0
0.2
0.4
0.6
0.8
0.43
0.21
0
0.2
0.4
0.6
0.8
n = 149 n = 138 n = 431n = 160 n = 166 n = 429
Overall TRANSFORMS population***
AR
R
AR
R
AR
R
-0.22 or -52% vs. IFNβ-1a IM
p<0.001
-0.31 or -61% vs. IFNβ-1a IM
p<0.001
-0.31 or -61% vs. IFNβ-1a IM
p<0.001
Patients with highly active disease despite prior IFNβ (relapse and MRI criteria)*
IFNβ-1a IM Fingolimod 0.5 mg
Subgroups relevant to the approved EU label
FIN12-C117Date of preparation September 2012
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TERIFLUNOMIDE Selective and reversible inhibitior DHODH dihydro-orotate
dehydrogensae Mitoch enzyme Inhibits proliferation B/T cells Approved FDA 2012 2 phase 3 trials TEMSO/TOWER/TOPIC/TENERE N=1088 ARR 31% SAD 30% (27-31%)
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Annualized Relapse Rate and Sustained Disability
Progression.
TEMSOO'Connor P et al. N Engl J Med 2011;365:1293-1303.
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TOWER
2nd phase 3 trial terif 1+relapse 1yr 2+ 2yrs 48wks n=1169 70% completed study ARR -22.3% -36.3% Free relapses 55.4% v
37.7% SAD 22/21% v 15.8%
Alopecia 13% TENERE: no superiority
Rebif TOPIC - CIS
Effective, well tolerated, more long term safety data needed
2M pt-yrs in RA
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BG12/DMF
Anti inflamm antioxidative stress ?cytoprotective
DEFINE v pl /CONFIRM v pl v GLA Fox NEJM 2012
50% RR SAD 33%
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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
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Clinical Outcomes at 2 Years in the Intention-to-
Treat Population.
Fox RJ et al. N Engl J Med 2012;367:1087-1097.
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LAQUNIMOD
ALLEGRO 23% RR 36% SAD BRAVO More pronounced effect on disability than
RR??
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Clinical Outcomes and MRI Measures of Efficacy According to Study
Group.
ALLEGRO
Comi G et al. N Engl J Med 2012;366:1000-1009.
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Treatment Map
CIS RRMS HARRMS
ABCR
NATFING
ALEM
NEW ORALS
Monoclonals
Adapted from X Montalban ECTRIMS 2012
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Acknowledgements
Slideshare - Prof G Giovannoni Helen Durham Centre: Dr Katharine Harding Dr Mark Cossburn Prof Neil Robertson Dr Sebastian Luppe Dr Claire Hurst