dmt update ms life manchester 2014
TRANSCRIPT
DMT Update
Gavin Giovannoni
Barts and The London
The DMT pipeline
Interferons
Phase I
Phase II
Phase III
Marketed
Anti-proliferation agents
Avonex
Atacicept
Campath Rituximab
Novantrone
Rebif
Betaferon/ Extavia
Teriflunomide
Tysabri
Zenapax
Pixantrone
Targeted mAbs/Fc-Ab
Cladribine
Fingolimod
Azathioprine
= oral administration
= injectable
Riluzole
Symptomatic Tx
Vaccine, tolerisation
Tovaxin
ATL-1102
MM-093 BG12
AJM-300
Nerispirdine
Interferon Tau
Interferon omega
Peg IFNb (BIIB017)
Fc- IFb
ATX-MS-1467
Firategrast
Ofatumumab
Sativex
Lymphocyte trafficking
TBC4746
MLN-0002
Targeted Immune regulation
PI2301
R1295
Copaxone
Laquinimod
Fampridine SR
683699 (T-0047)
Ocrelizumab
LY-2127399
The ideal DMT
Therapeutic Ideal
Reliable
long-term efficacy
Maintaining
QOL
Maintaining
independence
Maintaining the
ability to work
No issue for
pregnancy/fertility
Maximum reduction
of MS disease activity
Maximum
tolerability
Maximum
safety
Ease of
use
Minor impact on
everyday life
Treatment strategy
Treat early and effectively
Natural history
Delayed intervention
Later treatment
Treatment at diagnosis
Early intervention
Time Disease Onset
Dis
abili
ty
Time is brain
Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFN-1b trial
Goodin et al. Neurology 2012;78:1315-1322.
Regular Medical Care*
Primary Endpoint: All cause mortality free survival comparison between IFNβ-1b 250 µg eod vs. placebo per ITT
*Group approximately matched between DMTs
IFB-beta-1b approved
N=372
250 mcg
50 mcg
Placebo
1988 1993 2005 2006 2009 2010
98.4% ascertainment
Pivotal Trial
16-Year LTF 21-Year LTF
Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFN-1b trial
Goodin et al. Neurology 2012;78:1315-1322.
Consequences of increasing EDSS scores: loss of employment
0
10
20
30
40
50
60
70
80
90
Work Capacity by Disability Level
0.0/1.0 2.0 3.0 4.0 5.0 6.0 6.5 7.0 8.0/9.0
EDSS Score
Pro
po
rtio
n o
f P
ati
en
ts ≤
65
Ye
ars
Old
Wo
rkin
g (
%)
The proportion of patients employed or on long-term sick leave is calculated as a percentage of patients aged 65 or younger.
1. Kobelt G et al. J Neurol Neurosurg Psychiatry. 2006;77:918-926;
2. Pfleger CC et al. Mult Scler. 2010;16:121-126.
Spain
Sweden
Switzerland
United Kingdom
Netherlands
Italy
Germany
Belgium
Austria
~10 yrs2
MS patient’s QoL decreases tremendously dependent on the EDSS score
Mean utility
Utilities at early
disease
Utility at severe disease
Austria 0.55 0.90 0.05
Belgium 0.51 0.85 0.06
Germany 0.62 0.86 0.10
Italy 0.53 0.80 0.06
Netherlands 0.61 0.85 0.05
Spain 0.55 0.87 0.08
Sweden 0.546 0.825 0.047
Switzerland 0.59 0.89 0.1
UK 0.51 0.92 0.18
EQ-5D was used to calculate utilities: Utility is a measure of people's well-being or preferences for outcomes.
Mean utilities and EDSS in Germany 1= perfect health; 0 = worst health/dead
Source: based on G. Kobelt et al.: The European Journal of Health Economics, Volume 7; suppl. 2006
Treatment strategies
A
B
C
D
E
N M
Y X Moderate
Efficacy
Intermediate
Efficacy
High
Efficacy
1st-line
2nd-line
3rd-line
Survival Analysis
“Hit hard and early”
MS is an autoimmune
disease hypothesis
15–20 year
experiment
What is your treatment philosophy?
How bad is MS?
Question: What prognostic group do you fall into? Potential Consequences of the Disease
www.ms-res.org
Monitoring is important
Predictors of long-term outcome in MSers treated with interferon beta-1a
Bermel et al. Ann Neuol 2012.
Bermel et al. Ann Neuol 2012.
Predictors of long-term outcome in
MSers treated with interferon beta-1a
Treatment vs. Natural History
MS is an iceberg?
Clinical
MRI
Pathology
Treat-2-target
No evident disease activity (NEDA)
NICE
The relapsing MS DMT doughnut
The relapsing MS DMT doughnut
Inactive RRMS
CIS
RIS or asymptomatic MS
Suboptimal responders ?
Active RRMS
Highly active RRMS
The relapsing MS DMT doughnut
Inactive RRMS
CIS
RIS or asymptomatic MS
Suboptimal responders ?
Active RRMS IFNbeta / GA IFNbeta / GA
Highly active RRMS Fingolimod Natalizumab
Current UK practice
100 MSers
Who are the responders?
~20% responders
~40% sub-optimal responders
~40% non-responders
Question: Do you have active MS?
vs
1
2
3
Clinical
MRI
Biomarkers
Giovannoni G. Barts & The London, UK, February 2014.
The reality
Relapsing-remitting MS (RRMS)
Active disease?
Randomise
RES disease?
Y
N
N
Rx with Nz
Observation
Y
Current practice T2T-NEDA
Current 1st-line treatments IFNb, GA (Teri, BG12)
Current 1st-line treatments IFNb, GA (Teri, BG12)
6-monthly* clinical F-UP
Clinical responder?
Y
N
HAD or RES?
N
Y
Escalation/switch to upper tier natalizumab, fingolimod
(Alemz)
Switch in lower tier IFNb, GA
(Teri, BG12)
6-monthly* clinical/MRI F-UP
Clinical/MRI responder?
Y
N
Escalation/switch in upper tier natalizumab, fingolimod
(Alemz)
3-yr 1° outcome: confirmed disability progression 5-yr 1° outcome: time to confirmed EDSS 4.0
2° outcomes: MRI etc.
PROPOSED NEDA Rx Trial
NEDA = No Evident of Disease Activity T2T = treat-2-target
RES = rapidly evolving severe MS HAD = highly-active disease activity
* A clinical relapse between 6-monthly visits will trigger an unscheduled assessment for switching/escalation
GG, version 1.0 3rd Jan 2014
Treating-2-target
Choosing therapy
X Y Z
Define the
Individual’s MS
No
Treatment failure? Yes
• Patient’s preferences?
• Your choice?
Individual measures:
• Evidence of disease activity?
• Tolerability/safety?
• Adherence?
• Drug or inhibitory markers?
Monitoring
• MS prognosis
• Life style and goals
• Shared goals for therapy
Rebaseline
Rebaseline:
• IFNβ, natalizumab, fingolimod,
teriflunomide, DMF=3-6 months
• Glatiramer acetate=9 months
• Alemtuzumab=24 months
DMF=dimethyl fumarate.
DMT Summary
Efficacy
Ris
ks
+
+ -
-
GA
BMT
Mx
Alemz
aCD20
Lq BG12
Dac
Nz JCV+
Nz JCV-
IFNb Teri
Not licensed (but available in the NHS)
Licensed (available in the NHS)
Licensed (not available via NHS yet)
Late stage development (phase 3)
Fingo
KEY
DMT SUMMARY
What about pregnancy?
Questions MSers ask about pregnancy 1. Does MS affect my fertility?
2. Will pregnancy affect the course of my MS?
3. Will I be able to breast feed after delivery?
4. How long before I fall pregnant must I stop my DMT?
5. If I fall pregnant on a DMT will this affect the baby?
6. Can I breast feed on my DMT?
7. Will I be able to be a good parent if I become disabled from my MS?
8. If I become disabled or unemployed as a result of MS will I be able to support my children?
9. What is the risk of my children getting MS?
10. Can I do anything to prevent them from getting MS?
11. Am I more likely to need an assisted delivery because I have MS?
12. Will I be able to have a normal vaginal delivery?
13. Will I be able to have an epidural during labour?
14. How you treat hyperemesis gravidarum during pregnancy?
15. Should I continue taking my other drugs for my MS symptoms during pregnancy?
16. What is the best treatment strategy for my MS? Should I go onto a DMT and get my MS under
control before starting a family or should I first start my family?
17. What is the best treatment strategy for my MS to maximise my chances of having a family and
keeping my MS under control?
18. How will having neutralizing anti-interferon beta antibodies affect my baby?
19. Can I have IVF? Will the drugs that are used to induce ovulation affect my MS?
20. What dose of vitamin D do you advise during pregnancy?
21. Are oral contraceptive safer for my MS? Which contraceptive do you recommend?
What about vitamin D?
The effect of vitamin D-related interventions on multiple sclerosis relapses: a meta-analysis
James et al. Mult Scler. 2013 Oct;19(12):1571-9.
There is no evidence that vD supplements modify the course of MS. Low vD levels in MS can be due to reverse causation, i.e.
MS results in low vD levels.
Osteopaenia: z-scores are lower in MSers
Lumbar spine Femoral neck (NS)
Dobson et al. Mult Scler. 2012 Nov;18(11):1522-8.
The future?
Preventing end-organ damage
Control Multiple sclerosis
Brain atrophy occurs across all stages of the disease
De Stefano, et al. Neurology 2010
n= 963 MSers
Treatment Effect on Disability Strongly Predicted by Effect on T2 Lesion Volume and Brain Atrophy, Combined
Meta-analysis of treatment effect on EDSS worsening (y) vs effects on
MRI lesions and brain atrophy, individually or combined, in 13 placebo-
controlled RRMS trials (13,500 patients)
Sormani MP et al. Ann Neurol. 2014;75:43-49.
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1250
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1350
1400
1450
1500
30 35 40 45 50 55 60 65 70 75 80
Bra
in V
olu
me
(m
L)
Age (years)
Brain atrophy curves
Lower limit of normal
Average
Upper limit of normal
Hypothetical treatment effects
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Bra
in V
olu
me
(m
L)
Age (years)
Brain atrophy curves
MS lower limit
MS Average
MS Upper limit
-5%
-30%
Hypothetical treatment effects
Fingolimod has an early and sustained effect on the rate of brain atrophy compared with placebo and IFNb-1a IM
FREEDOMS, 2 years
Fingolimod 0.5 mg (n = 356)
Placebo (n = 329)
***
* **
6 0 12 24
Time (months)
0
-0.4
-0.8
-1.2
-1.6
-2.0
−38%
vs placebo p<0.001
Ch
ange
in m
ean
BV
fro
m
bas
elin
e (%
)
TRANSFORMS, 1 year
0 12
Time (months)
0.0
-0.4
-0.6
-1.0
IFNb-1a IM (n = 359)
Fingolimod 0.5 mg (n = 368)
−40%
vs IFNb-1a IM p<0.001
*** -0.2
-0.8
Ch
ange
in m
ean
BV
fro
m
bas
elin
e (%
)
ITT population with evaluable MRI images. Note: n numbers for FREEDOMS data reflect the number of patients with available data at 24 months. *p<0.05; **p<0.01; ***p<0.001 vs comparator; p-values are for comparisons over Months 0-6, Months 0-12, Months 0-24 BV, brain volume; ITT, intent-to-treat. Gilenya™ Prescribing Information 19 April 2012. Reproduced with permission. Kappos L et al. N Engl J Med 2010; 362: 387-401, and Cohen JA et al. N Engl J Med 2010; 362: 402-415. Copyright © 2011 Massachusetts Medical Society. All rights reserved
-1.0%
-0.8%
-0.6%
-0.4%
-0.2%
0.0% Years 0-2
-0.82%
-0.80%
P=0.822†
Placebo (N=315) Natalizumab (N=627)
Year 0-1* Year 1-2
-0.40%
-0.56%
-0.43%
-0.24%
P=0.004†
P=0.002†
†Difference between treatments; ‡Change from baseline; Miller DH et al. Neurology 2007;68:1390-1401.
AFFIRM Study: natalizumab and brain atrophy
Mean
(S
E)
perc
en
tag
e c
han
ge i
n B
PF
-5%
-30%
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Bra
in V
olu
me
(m
L)
Age (years)
Brain atrophy curves
MS Average
Hypothetical treatment effects
-5%
-20%
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Bra
in V
olu
me
(m
L)
Age (years)
Brain atrophy curves
late treatment
Hypothetical treatment effects
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Bra
in V
olu
me
(m
L)
Age (years)
Brain atrophy curves
-5%
-18%
early treatment
late treatment
Hypothetical treatment effects
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Bra
in V
olu
me
(m
L)
Age (years)
Brain atrophy curves
-5% -11%
early very
highly-effective
treatment
late very
highly-effective
treatment
-15%
Hypothetical treatment effects
Conclusions 1. Current 1st-line or platform therapies are only moderately effective
a. Safe, but are associated with troublesome side effects and poor adherence
2. Escalation therapies (Fingolimod, Natalizumab & Mitoxantrone)
a. More effective but potential for more serious adverse effects
b. Tools and strategies have been developed to optimise risk:benefit; e.g natalizumab (PLEX & JCV
serology)
3. Emerging therapies
a. oral agents
i. Fingolimod – currently 2nd-line, may promote remyelination; if PPMS trial positive major
advantage over other emerging oral therapies (the halo effect)
ii. Teriflunomide – 1st-line therapy with a predictable SE profile based on the RA drug
leflunomide (the tortoise)
iii. BG12 or DMF – 1st-line, higher efficacy, interesting mode of action; ideal for combination
therapy (potential combi-tab)
iv. Laquinimod – not that effective as an anti-inflammatory, but has the neuroprotective
effects (the dark horse, ultimate combi-tab)
b. Alemtuzumab, 1st, 2nd or 3rd line; most potent of the DMTs but associated with risks
c. Daclizumab (biomarker) and anti-CD20 most exciting of the parenteral therapies in development
4. Patient factors ; risk assessment tools, education and a focus on wellness
5. Neuroprotection – several phase 2 trials currently been undertaken with oral agents
6. New target preventing end-organ damage