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Slides from my debate in Dublin on Friday 17th October 2014.
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All patients on an injectable should be switched to an oral
Bates (pro) vs. Giovannoni (against)
Professor Gavin Giovannoni
Blizard Institute, Barts and The London School of Medicine and Dentistry
All patients on an injectable should be switched to an oral
Bates (pro) vs. Giovannoni (against)
Professor Gavin Giovannoni
Blizard Institute, Barts and The London School of Medicine and Dentistry
Disclosures Professor Giovannoni has received personal compensation for participating on Advisory Boards in relation to clinical trial design, trial steering committees and data and safety monitoring committees from: Abbvie, Bayer-Schering Healthcare, Biogen-Idec, Canbex, Eisai, Elan, Fiveprime, Genzyme, Genentech, GSK, GW Pharma, Ironwood, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals.
Regarding www.ms-res.org survey results in this presentation: please note that no personal identifiers were collected as part of these surveys and that by completing the surveys participants consented for their anonymous data to be analysed and presented by Professor Giovannoni.
Professor Giovannoni would like to acknowledge and thank Biogen-Idec, Genzyme and Novartis for making available data slides on natalizumab, alemtuzumab and fingolimod for this presentation.
Why switch?
Why would you switch from an injectable?
1. Stable on treatment: no evident disease activity, no concerns
2. Stable on treatment: poor tolerance
3. Stable on treatment: poor adherence
4. Stable on treatment: want to fall pregnant
5. Breakthrough disease: suboptimal efficacy
No
Yes
Yes
Yes
Yes
But, why only an oral?
What is the aim of our treatments?
www.ms-res.org
Consequences of increasing EDSS scores: loss of employment1
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
Quality of life and disability
MS is one of the most common causes of neurological disability in young adults2
Natural history studies indicate that it takes a median time of 8, 20 and 30 years to reach the irreversible disability
levels of EDSS 4, 6 and 7, respectively3
Up to 75% increased annualized divorce rate4
Life expectancy is reduced by 5-10 years5
7.5x greater than suicide rate than the general population6
2 out of 3 patients with RRMS were unemployed due to the disease7
Utilit
y
EDSS Status
EDSS and utilitya show a significant inverse relationship1,b
aUtility measures are derived from EQ-5D using the EuroQoL instrument. bAdapted from Orme et al 2007. Error bars depict 95% confidence intervals. Half points on EDSS are not shown on graph axis, except at EDSS 6.5.
1.Orme M et al. Value In Health. 2007;10:54-60. 2.WHO. 2008.[TK] 3. Confavreaux, Compston. 2005.[TK] 4. Coles et al. 2001.[TK] 5. Confavreaux, Vukusic. 2006.[TK] 6. Sadovnick et al. Neurology 1991;41:1193-6.
7. Morales-Gonzales. Mult Scler. 2004;10:47-54.
No evident disease activity: NEDA
Gd, gadolinium. 1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et al. Lancet Neurol 2011; 10:329–337.
Treat-2-target
No evidence of disease activity defined as:1,2
× No relapses
× No sustained disability progression
× No MRI activity
× No new or enlarging T2 lesions
× No Gd-enhancing lesions
Bermel et al. Ann Neuol 2012.
Predictors of long-term outcome in
MSers treated with interferon beta-1a
MRI to monitor treatment response to IFNβ: a meta-analysis
Dobson et al. Neurology 2013.
Study or Subgroup Odds Ratio
IV, Random, 95% CI
Kinkel 2008
Prosperini 2009
Total (95% CI) 9.86 (2.33, 41.70)
Study or Subgroup Odds Ratio
IV, Random, 95% CI
Kinkel 2008
Pozzilli 2005
Prosperini 2009
Sormani 2011
Total (95% CI) 2.69 (0.72, 10.04)
0.01 0.1 1 10 100 Disease Less Likely Disease More Likely
One New T2 Lesion
Favors Experimental Favors Control
100 10 1 0.1 0.01
Two or More New T2 Lesions
Study or Subgroup Odds Ratio
IV, Random, 95% CI
Kinkel 2008
Rio 2008
Total (95% CI) 5.46 (2.48, 12.04)
MRI to monitor treatment response to IFNβ: a meta-analysis
Study or Subgroup Odds Ratio
IV, Random, 95% CI
Kinkel 2008
Pozzilli 2005
Tomassini 2006
Total (95% CI) 3.34 (1.36, 8.22)
0.01 0.1 1 10 100 Disease Less Likely Disease More Likely
One New Gd+ Lesion
0.01 0.1 1 10 100
Disease Less Likely Disease More Likely
Two or More New Gd+ Lesions
Dobson et al. Neurology 2013.
Relapses
Unreported relapses
Clinical disease progression
Subclinical relapses: focal MRI activity
Focal gray and white matter lesions not detected by MRI
Brain atrophy
Spinal fluid neurofilament levels
MS Iceberg
Clinical activity
Focal MRI activity
Hidden focal and diffuse MRI activity
Microscopic or biochemical pathology
Biomarkers
Control Multiple sclerosis
Brain atrophy occurs across all stages of the disease
De Stefano, et al. Neurology 2010
n= 963 MSers
Association of MRI metrics and cognitive impairment in radiologically isolated syndromes
Amato et al. Neurology. 2012 Jan 31;78(5):309-14.
AAN 2013
AAN 2013
Reduced head and brain size for age and disproportionately smaller thalami in child-onset MS
Kerbrat Neurology. 2012 Jan 17;78(3):194-201.
Treatment effect on disability predicted by effect on T2-lesion load and brain atrophy
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.
-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
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
Reduction in brain atrophy on alemtuzumab
Rheumatoid arthritis End-stage joint disease
IFNbeta
GA
Teri
DMF
Treatment Ladder
DMF Fingo
Nz Az
x
x
x x
IFNbeta
GA
Teri
DMF
Treatment Ladder
DMF Fingo
Nz Az
Relapses
Unreported relapses
Clinical disease progression
Subclinical relapses: focal MRI activity
Focal gray and white matter lesions not detected by MRI
Brain atrophy
Spinal fluid neurofilament levels
MS Iceberg
Clinical activity
Focal MRI activity
Hidden focal and diffuse MRI activity
Microscopic or biochemical pathology
Biomarkers
Why?
Adherence
• In MS, patients with long gaps in treatment are at greater risk of relapse than more adherent patients1
• Lower adherence to MS therapy is associated with a higher risk of relapse2
Treatment gaps and poor adherence are associated with increased relapse rates
Adherence is one of the keys to optimizing outcomes
1. Al-Sabbagh A et al. J Neurol 2008;255(Suppl. 2):S79 2. Steinberg SC et al. Clin Drug Invest 2010;30:89-100. Copyright © 2010, Adis Data Information BV MPR, Medication Possession Ratio
Comparison of relapse risk ratios by level of adherence in patients with MS2
80 <80 <75 <70 <65 <60 0.90
0.95
1.00
1.05
1.10
1.15
Rel
apse
ris
k ra
tio
MPR (%)
Forgetfulness is a primary cause of non-adherence
Pain at injection site
Not confident in treatment benefits
Other
Headache
Skin reaction
Depression
Financial reasons
Forgot to administer
Flu-like symptoms
Injection anxiety
Dosing schedule difficult/inconvenient
Weakness
Did not pick up medicine
Nobody available to administer
Pregnancy/planned pregnancy
Did not feel need for injection
Tired of taking injections
Fatigue
50%
20%
17%
15%
13%
12%
10%
10%
10%
9%
8%
6%
5%
4%
3%
2%
2%
1%
0 20 40 60 Patients (%)
Re
aso
ns
for
mis
sin
g o
ne
or
mo
re in
ject
ion
s
Psychological factors – forgetfulness and complacency
– impact adherence
Observational GAP study
Devonshire V et al. Eur J Neurol 2011;18:69-77 Patients could have reported more than one reason for non-adherence. When counting injection-related reasons for non-adherence, each patient was counted only once. GAP, Global Adherence Project
Do really think a tablet is going to improve poor adherence?
Alemtuzumab pharmacokinetics in MS
Clinical effects persist after Alemtuzumab is cleared from circulation
• Alemtuzumab serum concentrations low or undetectable within ~30 days after treatment
Alemtuzumab 12 mg administered at time 0 and 12 months.
Kovarova I, et al. Presented at: European Neurological Society; 2012; Prague; P341.
CARE-MS I: Mean Serum Concentration Over Time
Time on Study, mo
4,000
0
2,000
3,000
1,000
0 1 3 6 9 12 24 15 18 21
Co
nce
ntr
ation
(n
g/m
L)
13
Alemtuzumab
12 mg
Alemtuzumab 12 mg
Why?
Pregnancy
Considerations for Women of Childbearing Potential
Interferon β • In monkeys, increased rate of abortion. No malformations in
surviving animals
• Initiation of treatment is contraindicated during pregnancy
Glatiramer acetate
• Animal studies are insufficient with respect to effects on pregnancy;
embryonal/foetal development, parturition, and postnatal
development
• Contraindicated during pregnancy / registers indicate it is safe
Natalizumab
• Studies in guinea pigs and monkeys showed no evidence of
teratogenic effects or effects on growth of offspring
• Should not be used during pregnancy unless the clinical condition of
the woman requires treatment with natalizumab
Fingolimod
• Animal studies have shown reproductive toxicity, including foetal loss
and teratogenicity
• While on treatment, women should not become pregnant; if
pregnancy occurs, discontinuation of fingolimod is recommended
CO-CZ-0056b
Data from summary of product of characteristics (SmPC) for each therapy.
Considerations for Women of Child-bearing Potential
Teriflunomide
• Embryotoxic and teratogenic in rats and rabbits at doses in the
human therapeutic range
• Contraindicated in pregnancy
• Patient advised to contact physician if pregnancy is suspected;
institution of accelerated elimination may decrease risk to foetus
Alemtuzumab
• Dosing mice for 5 days during gestation resulted in significant
increases in dead or resorbed conceptuses and reduction in viable
foetuses
• Placental transfer and potential pharmacologic activity observed
• Contraception advised during treatment and for 4 months following
• Should be administered during pregnancy only if the potential benefit
justifies the potential risk to the foetus
• Thyroid disease poses special risks in women who are pregnant
(potential miscarriage, foetal effects such as mental retardation and
dwarfism, transient neonatal Graves’ disease)
Dimethyl fumarate • No malformations have been observed at any dose in rats or rabbits
• Should be used during pregnancy only if clearly needed and if the
potential benefit justifies the potential risk to the foetus
CO-CZ-0056b
Data from summary of product of characteristics (SmPC) for each therapy.
Alemtuzumab pharmacokinetics in MS
Clinical effects persist after Alemtuzumab is cleared from circulation
• Alemtuzumab serum concentrations low or undetectable within ~30 days after treatment
Alemtuzumab 12 mg administered at time 0 and 12 months.
Kovarova I, et al. Presented at: European Neurological Society; 2012; Prague; P341.
CARE-MS I: Mean Serum Concentration Over Time
Time on Study, mo
4,000
0
2,000
3,000
1,000
0 1 3 6 9 12 24 15 18 21
Co
nce
ntr
ation
(n
g/m
L)
13
Alemtuzumab
12 mg
Alemtuzumab 12 mg
There is only one other drug has a better pregnancy profile than alemtuzumab and that was cladribine?
Conclusions
• MS is a bad disease • Mortality, disability, unemployment, divorce, suicide cognitive
impairment, etc.
• New treatment paradigm • Early effective treatment
• Therapeutic ladder; early treatment with rapid escalation
• Maintenance vs. induction therapy • Adherence and pregnancy major discriminators
• Improved risk mitigation tools
• Treat-2-target of NEDA
• Prevent end-organ damage (brain atrophy & CSF NF levels)
• Sustained improvement (treat early)
• Protect reserve capacity (healthy ageing)
• Long-term remission
• Is there any reason why you would limit yourself to an oral therapy?
Why would you switch from an injectable?
1. Stable on treatment: no evident disease activity, no concerns
2. Stable on treatment: poor tolerance
3. Stable on treatment: poor adherence
4. Stable on treatment: want to fall pregnant
5. Breakthrough disease: suboptimal efficacy
No
Yes
Yes
Yes
Yes
But, why only an oral? I urge you to vote NO!
Treatment Selection & 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.
Gd
T2
CU
R
DP
15% vs 47% Δ 32%
13% vs 68% Δ 55%
6% vs 37% Δ 31%
Effect of natalizumab on clinical and radiological disease activity in MS: a retrospective analysis of the
Natalizumab Safety and Efficacy in Relapsing-Remitting MS (AFFIRM) study
Havrdova et al. Lancet Neurol. 2009 Mar;8(3):254-60.
Relapsing-MS
Active Inactive Highly-active Rapidly-evolving severe
What is active MS?
2001 Clinical
2009 Clinical and MRI
2014 Clinical or MRI
Active Inactive (NEDA or no evident disease activity) HA RES
What is your treatment aim?
2001 Clinical
2009 Clinical and MRI
2014 Clinical or MRI