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Defining suboptimal response to treatment in MS
Gavin Giovannoni
Barts and The London School of Medicine and Dentistry
London, UK
Disclosures
Professor Giovannoni has received personal compensation for participatingon Advisory Boards in relation to clinical trial design, trial steeringcommittees 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 VertexPharmaceuticals.
Professor Giovannoni would like to acknowledge several companies andcolleagues for making available data slides on for this presentation.
The changing treatment paradigm
IFNbeta
GA
Teri
DMFFingo
Nz
Az
Treatment Complexity
2014
7 IFNbeta
GA
Teri
DMF
FingoNz
Az
Dac
Anti-CD20
2016
9
100 MSers
Who are the responders?
?
40:60
?
80:20
What is active MS?
2001Clinical
2009Clinical and MRI
2014Clinical or MRI
Inactive MS: no relapses or MRI activity in the last 24 months
Active MS: relapses in the last 12 or 24 months and/or MRI activity in the last 12 months
Eligibility for treatment
2001Clinical
2009Clinical and MRI
2014Clinical or MRI
Inactive MS: no relapses or MRI activity in the last 24 months
Active MS: relapses in the last 12 or 24 months and/or MRI activity in the last 12 months
Highly active MS: relapses in the last 12 months and MRI activity in the last 12 months
Rapidly-evolving severe MS (RES); two disabling attacks in a 12
month period and MRI evidence of activity during this period.
No treatmentNatalizumab
(Tysabri)Fingolimod
(Gilenya)Treatment
Aim of treatment
2001Clinical
2009Clinical and MRI
2014Clinical or MRI
Inactive MS: no relapses or MRI activity in the last 24 months (NEDA)
Active MS: relapses in the last 12 or 24 months and/or MRI activity in the last 12 months
Highly active MS: relapses in the last 12 months and MRI activity in the last 12 months
Rapidly-evolving severe MS (RES); two disabling attacks
in a 12 month period and MRI evidence of activity during
this period.
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 What is NEDA?
× No relapses× No sustained disability progression (EDSS)× No MRI activity
× No new or enlarging T2 lesions× No Gd-enhancing lesions
DAF1,2
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
Rapid vs. Slow escalation
IFNbeta
GA
Teri
DMF
Treatment Ladder
DMF
Fingo
Nz Az
Early treatment with fingolimod improved time to confirmed relapse vs switching after 12 months
*Number of patients who completed the study during M36–48. #Interval non-completers are patients who did not continue to the next yearly time interval. For interval non-completers, M0–24 summarises the aggregate ARR from M0 to M24 for patients who discontinued during the interval of M12–24. M0–36 summarises the aggregate ARR from M0 to M36 for patients who discontinued during the interval of M24–36. M0–48 summarises the aggregate ARR from M0 to M48 for patients who discontinued during the interval of M36–48. Cohen JA et al. J Neurol Neurosurg Psychiatry 2015
Time to first confirmed relapse up to the end of study (core ITT population)
Fingolimod increased the proportion of patients achieving NEDA after switching from IFNβ-1a
Data presented are for the pooled fingolimod 0.5 and 1.25 mg groups. N, total number of patients in the group; n, number of patients achieving NEDA; IFN, interferon; NEDA, no evidence of disease activity (defined as no relapses, no 3-month disability progression and no MRI activity). Cohen JA et al. J Neurol NeurosurgPsychiatry 2015
Comparison of NEDA status in the core study and the first extension year by treatment group
IFN-switch group Continuous-fingolimod group
IFNβ-1a fingolimod
Escalation to natalizumab is more effective than switching between IFN/GA
0
25
50
75
100
% P
ati
en
ts
Escalate to Natalizumab, n=106
Switch Between IFN/GA, n=161
Data from a postmarketing, prospective, observational study in 285 RRMS patients for whom treatment with IFNβ or GA therapy failed. After failure of IFNβ or GA therapy, patients were switched to either natalizumab (n=106) or IFNβ/GA (n=161). *There were no differences at 12 month between the two groups in proportions of patients free from relapse, disability progression, MRI activity, and combined activity.Prosperini L et al. Mult Scler. 2012;18:64-71.
No EDSS Progression
No MRIActivity
Disease Activity Free
P<0.0001 P=0.0003 P<0.0001
51
36
51
21
83
6777
59
NoRelapses
P<0.0045
Over 24 months*
65.4
87.3
52.9
32.2
46.7
78.9
31.5
13.60
25
50
75
100
Relapse-Free SAD-Free (6-month) MRI Activity-Free MS Disease Activity-Free
Alemtuzumab 12 mg
SC IFNβ-1a 44 μg
Escalation to Alemtuzumab Is More Effective Than Switching from IFN/GA to IFNβ-1a 3×/Week
OR=odds ratio; SC=subcutaneous; SAD=sustained accumulation of disability.Hartung HP et al. Presented at AAN; March 16–23, 2013; San Diego, CA. P07.093.
% o
f P
ati
en
ts
CARE-MS II: Disease-Free Status over 2 Years
OR=3.03P<0.0001
He et al. JAMA Neurol. 2015 Apr;72(4):405-13.
Comparison of switch to fingolimod or GA in active MS
TOP: earlier natalizumab treatment favours annualised relapse rate outcomes
P values from a negative binomial regression model adjusted for gender, baseline EDSS score (<3.0 vs ≥3.0l), relapse status in the prior year (≤1 vs>1), prior DMT use (<3 vs ≥3), disease duration (<8 vs ≥8 years), and treatment duration (≥3 vs <3 years), except for the factor of interest. Error bars represent 95% CIs.DMT=disease-modifying therapy; CI=confidence interval.Wiendl et al. Presented at ENS; June 8–11, 2013; Barcelona, Spain,. P372.
NEDA outcomes with alemtuzumab:3-year follow-up of the CARE-MS studies
MRI, magnetic resonance image; CI, confidence interval.
Adapted from Havrdova E et al. Presented on ACTRIMS/ECTRIMS, 2014, FC1.4.
384650
67 64
0
20
40
60
80
100
Year 1 Year 2 Year 3
Pro
po
rtio
n o
f p
ati
en
ts, %
(9
5%
CI) ↑32.2%
P=0.0062
↑45.8%P<0.0001
CARE-MS I: NEDA by year
SC IFNB-1a
ALEM 12 mg
174
369
170
356
—
349
SC IFNB-1a
ALEM 12 mg
187
405
173
434
—
393
27 31
44
56 55
0
20
40
60
80
100
Year 1 Year 2 Year 3
Pro
po
rtio
n o
f p
ati
en
ts, %
(9
5%
CI) ↑61.2%
P<0.0001
CARE-MS II: NEDA by year
↑84.3%P<0.0001
ECTRIMS 2013
TEMSO & TOWER: Evaluation of the Effect of Teriflunomidein Subgroups Defined by Prior Treatment (Pooled Analyses)
Adjusted ARR by Prior Treatment Disability Progression by Prior Treatment
ARR, annualized relapse rate; DMT, disease-modifying therapy; RRMS, relapsing-remitting MS.Adapted from Freedman M et al. Presented on ACTRIMS/ECTRIMS, 2014, P046.
An
nu
aliz
ed r
elap
se r
ate
Pro
bab
ility
of
dis
abili
ty p
rogr
essi
on
0.423 0.464 0.3030.463 0.536 0.3290.794 0.641 0.4720.0
0.2
0.4
0.6
0.8
1.0
>1 Prior DMT 1 Prior DMT No Prior DMT
0.072 0.201 0.1780.218 0.345 0.1760.298 0.299 0.2380.0
0.1
0.2
0.3
0.4
>1 Prior DMT 1 Prior DMT No Prior DMT
Teriflunomide 14 mgTeriflunomide 7 mgPlacebo
46.7%
41.6%27.7%
16.4%35.9%
30.2%
78.6%
33.4%
46.6%
5.0%
17.4%
20.8%
Patients (n) 41 32 36 189 193 192 498 547 523 Patients (n) 41 32 36 189 193 192 498 547 523
Post hoc analysis of pooled data of ARR and 12-week confirmed disability progression conducted on patient subgroups defined by prior MS therapy
End-organ damage
Baseline Month 6
Month 12 Month 18
Baseline Month 6
Month 12 Month 18
Patient 1 Patient 2
End-organ damage
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.
No evidence of disease activity: NEDA-4
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
How do we add a brain atrophy metric to our definition of NEDA?
Normalisation of brain atrophy rates
• For all annual BVL thresholds, significantly more NEDA-4 patients were in the fingolimod-treated group than in the placebo group
Results: NEDA-4 by Annual BVL Thresholds
aORs were derived from logistic regression of freedom from disease activity on treatment.Kappos et al. ACTRIMS/ECTRIMS 2014. FC1.5
Alemtuzumab Slows Brain Volume Loss Over 4-yrs Despite Most RRMS Patients Not Receiving Treatment for 3 Years
Coles et al. AAN 2015, P7.263
CARE-MS I CARE-MS II
Case study
Residual deficits:• Walking distance >500m• Unable to run • Exercise induces intermittent
sensory symptoms in L arm• Mild urinary frequency
17-yr girl, myelitis
Jun-2000
1st-yr University L-optic neuritis
Feb-2001
clumsy left hand
Jan -2002
pins & needles in legs
Oct-2003
R optic neuritis
Mar-2004
Brainstem syndrome;
diplopia and ataxia
Dec 2007
Cervical cord relapse
weak L arm with pain
Jan 2008
Bladder dysfunction
depression, anxiety and
fatigue
Reduced mobility
Mild urinary frequency
No depression ,anxiety or fatigue
Fully mobile
NEDA (no evident disease activity)
Feb-2008 to May-2014
IFN-beta
Feb-2001
Natalizumab
Jan-2008
ED
SS
IFN-beta NatalizumabJun-2000 May-2014
6.0
3.5 3.5
MRI – progressive brain atrophy
Dec 2007 Jul 2010 Jul 2013
Is this patient in long-term remission?
Other discriminators
1. Safety (risk:benefit)
2. Tolerability
3. Adherence
4. Monitoring
5. Pregnancy
6. Regional / Cultural influences
7. Cost
8. Marketing
Treating to target in inflammatory bowel diseases
IMS, immunosuppressant; TNF, tumour necrosis factorReproduced from Gut, Ordás I, Feagan BG and Sandborn WJ, 1754–63, 2011 with permission from BMJ Publishing Group Ltd.
Conventionalstep care
TNFantagonist
± IMS
Corticosteroids+ IMS
Corticosteroids
Corticosteroids+ IMS
Corticosteroids
TNFantagonist
± IMS
TNFantagonist
± IMS
Corticosteroids+ IMS
Conventionalstep care
TNFantagonist
± IMS
Corticosteroids+ IMS
Corticosteroids
Conventionalstep care
Acceleratedstep care
Moderate
Severe
IMS + TNFantagonist
Early top-down
Le
ve
l of
dis
ea
se
Flipping the pyramid
BARTS-MS T2T-NEDA ALGORITHM T2T = treating-to-target; NEDA = no evident disease activity
Choose therapy
A B C
Define the individual’s MS
Treatment failure?
• Patient’s preferences?• Your choice?
Individual measures:• Evidence of disease activity?• Tolerability/safety?• Adherence?• Drug or inhibitory markers,
e.g. NABs?
Monitoring
• MS prognosis based on clinical and MRI indices
• Life style and goals • Shared goals for therapy
Rebaseline
Rebaselining:• IFNβ, natalizumab, fingolimod,
teriflunomide, Dimethyl-Fumarate=3-6 months
• Glatiramer acetate=9 months• Alemtuzumab=24 months
Choose a therapeutic strategy
Maintenance-escalation Induction
Choose therapy
X Z
Rebaseline
Monitoring
Initiate or Switch or Escalate Rx Complete course / Re-treat
Breakthrough disease
Y
• Patient’s preferences?• Your choice?
NoYes Yes
• Only one licensed induction therapy at present
IFNβ = interferon-beta; NABs = neutralizing antibodies; Rx = treatment
Adoption of innovations
Rapid adoption of innovations is “biggest unmet need of all”
Adapted from Everett M. Rogers, Diffusion of Innovations
Large disparities exist in access to disease-modifying therapies
1. Hollingworth S et al. J Clin Neurosci 2014;21:2083–7; 2. World Bank, 2015. http://data.worldbank.org/indicator/SP.POP.TOTL; 3. MSIF, 2013. http://www.atlasofms.org; 4. Wilsdon T et al. 2013. http://crai.com/sites/default/files/publications/CRA-Biogen-Access-to-MS-Treatment-Final-Report.pdf
Australia
Norway
Denmark
Sweden
Belgium
Austria
Germany
France
Finland
Spain
Italy
Slovenia
United Kingdom
Poland
0 20 40 60 80 100
Newer DMT
Established DMT
No DMT
All people with MS (%)
All data are from 2013
4
4
4
4
4
4
4
4
4
4
4
4
4
1–3
Established DMTsDMTs approved for relapsing forms of MS during the 1990s and reformulations or generic versions of these substances.
Newer DMTsDMTs approved for relapsing forms of MS that have a different mechanism of action from established DMTs.
1st line
2nd line
3rd line
www.msbrainhealth.org
www.msbrainhealth.org
Conclusion
• DMT landscape is becoming increasingly complex
– Changing role of nurse specialists and MSologist
• New tools are required to engage MSers in treatment decisions
– Is it time to develop treatment algorithms?
• Treat-2-target of NEDA current paradigm
– NEDA (zero-tolerance) vs. MEDA
– Expand to include end-organ damage metrics, e.g. BVL (NEDA-4)
• Most sequencing decisions are not evidence-based
– scientific rationale
– registries and real-life data
– Head-2-head studies are needed
• Efficacy is not everything don’t forget safety , i.e. the risks and the benefits, tolerability, adherence, monitoring, pregnancy, etc…..
• Evidence-based stopping criteria
• Rapid adoption of innovations
• Holistic management of MS
– Brain Health, lifestyle issues, comorbidities, wellness, etc.
Questions