defining goals and patient expectations
TRANSCRIPT
Defining Goals and Patient Expectations
International MS Physician Summit Prague, 22nd-23rd March 2014
Gavin Giovannoni
Barts and The London
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. I would like to acknowledge Mark Hughes, from Infusion, who helped me prepare some of my slides. Please note that Professor Giovannoni’s attendance at the 2014 MS Physician Summit, in Prague, was sponsored by Biogen-Idec.
Employment
50% of patients with MS are
unemployed 10 years after
diagnosis5
Relationships
Compared with general population,
patients with MS have a higher
probability of separating/divorcing
and doing so sooner5
Mortality
Mortality ratio of MS exceeds
CV disease,2,b stroke,3,c and
early breast cancer4
Healthcare costs
Bulk of cost attributed to services
(29%) and long-term sick leave
and early retirement (30%)6,d
QOL
EDSS and utilitya have
shown a significant inverse
relationship1
MS Is a Disabling Disease
MS=multiple sclerosis; QOL=quality of life; EDSS=Expanded Disability Status Scale; CV=cardiovascular; EQ-5D=EQ-5D=EuroQol 5-Dimension questionnaire. 1. Orme M et al. Value Health. 2007;10:54-60. 2. De Marco R et al. Diabetes Care. 1999;22:756-761. 3. Petty DW et al. Mayo Clin Proc. 2005;80:1001-1008. 4. Hooning MJ et a. Int J Radiat Oncol Biol Phys. 2006;64:1081-1091. 5. Pfleger CC et al. Mult Scler. 2010;16:121-126. 6. Berg J et al. Eur J Health Econ. 2006;7 (suppl 2):S75-S85.
a. Utility measures derived from EQ-5D b. In patients with type 2 diabetes c. In patients with valvular heart disease
in Olmsted County, Minnesota d. MS patients with EDSS ≥6.0
MS has a negative
impact on…
Utility (QoL) Scores Make Diseases Comparable
0.45
0.55
0.60
0.75
0.80
0.65
0.70
0.50
0.72 – Mean utility of patients with rheumatoid arthritis
at stage 12
0.00 – Worst
possible health
status
1.00 – Best
possible health
status
0.55 – Mean utility of patients with MS4
0.48 – Mean utility of severe haemophilia patients with inhibitors5
0.82 – Mean utility of aging patients with osteoporosis,
no fracture1
0.58 – Mean utility of patients with Parkinson’s disease3
1. Oleksi A et al. J Bone Miner Res. 2000;15:1384-1392; 2. Holbelt G et al. Arthritis Rheum. 1999;42:347-356;
3. Siderowf A et al. Neurology. 2002;59:103-108; 4. Kobelt G. et al. Eur J Health Econ. 2006;7:S5-S104;
5. Ekert H et al. Haemophilia. 2001;7:279-285.
MS Patients’ Quality of Life Decreases Tremendously, Dependent on EDSS
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 0.55 0.83 0.05
Switzerland 0.59 0.89 0.10
UK 0.51 0.92 0.18
EQ-5D was used to calculate utilities: Utility is a
measure of a person's well-being or preferences for
outcomes
Mean Utilities and EDSS in Germany 1= Perfect health; 0 = Worst health/dead
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Mean
Uti
lity
(E
Q-5
D)
EDSS
Kobelt G et al. Eur J Health Econ. 2006;7:S5-S104; Kobelt G et al. Eur J Health Econ. 2006;7:S34-S44.
Lessons Learned from Managing RRMS and Two Decades of Disease-Modifying Therapies
Disability progression in two phases Treatment changes the disease course
In RRMS, gender, age at onset, residual
deficit after the first relapse, and relapses
during the first 2 years are independent
predictors of disability progression only in
phase 1
DS
S S
co
re
Years from clinical onset of MS
6
5
4
3
2
1
0 0 5 10 15 20 25 30
7
Phase 2
Phase 1
Treatment (IFNβ) Impact2
Pro
ba
bilit
y o
f S
PM
S
0.05
0.10
0.15
0.20
0.25 Untreated
Treated
1 2 3 4 5 6 7
Follow-up Years
0
Natural History1
Propensity score-adjusted survival curves
for time from first visit to secondary
progression. Cumulative probability
represents the estimated proportion of
patients reaching the end point
1Data from a retrospective, database review of the Rennes MS database showing the 718 MS patients who had reached both DSS 3 and 6;
these were divided into five subgroups defined according to the duration of phase 1 (mean time from MS clinical onset to DSS 3).
DSS=disability status scale; RRMS=relapsing remitting MS; SPMS=secondary progressive MS; IFNβ=interferon beta.
1. Leray E et al. Brain 2010;133:1-14. 2. Trojano M et al. Ann Neurol. 2007;61:300-306.
Survival Analysis
“Hit hard and early”
MS is an autoimmune
disease hypothesis
15–20 year
experiment
What Is Your Treatment Philosophy? Will “Hit Hard and Early” Be Enough
Patient and Disease Profile
Shared Decision Making Involves Consideration of Many Factors
Shared
Treatment
Decision
Therapy Attributes
Patient Preferences
Geographic and Economic
Factors
Age, gender
Disease activity/disease type
Disability/functional impairment
Treatment history
Comorbidities
Efficacy
Safety
Tolerability
Administration (route/frequency)
Monitoring requirements
Biomarkers (eg, anti-JCV Ab, NAbs)
Socio-demographic profile (lifestyle,
work status, family status)
Convenience
Risk tolerance
Likelihood of adherence
Approved usage
Reimbursement/access to drug
Shared treatment decision
optimally weighs these
considerations to arrive at the
therapy that best meets the
patient’s needs
JCV=John Cunningham virus; Ab=antibody; Nab=neutralising Ab.
Managing to the Goals of Therapy Makes for a Stepwise Process
Monitoring:
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
Defining Shared Goals
• Physicians can objectively assess measureable disease outcomes. Targets are – Freedom from disease activity
– Long-term stability on EDSS
• Patients are interested in therapies that improve their ability to work, parent, socialise, and participate in life. Important outcomes for them are minimising changes in – Fatigue
– Cognition
– Mobility
– Bladder/sphincter control
– Sexual function
– QoL
Defining Shared Goals
• Physicians can objectively assess measureable disease outcomes. Targets are – Freedom from disease activity
– Long-term stability on EDSS
• Patients are interested in therapies that improve their ability to work, parent, socialise, and participate in life. Important outcomes for them are minimising changes in – Fatigue
– Cognition
– Mobility
– Bladder/sphincter control
– Sexual function
– QoL
“Zero Tolerance”
“Aim for Normality”
Escalation to Natalizumab Is More Effective Than Switching
Between IFN/GA
72
83
59 51 51
67
36
21
0
25
50
75
100
Pa
tie
nts
(%
)
Escalation to natalizumab, n=106
Switch between IFNβ/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).
*At 12 months, the two groups did not differ in proportions of patients free from relapse, disability progression, MRI activity, and combined activity.
PS-adj. HR=propensity score-adjusted hazard ratio.
Prosperini L et al. Mult Scler. 2012;18:64-71.
No EDSS
Progression
No MRI Activity Disease
Activity Free
PS-adj. HR: 0.42
P=0.002
PS-adj. HR: 0.56
P=0.006
PS-adj. HR: 0.51
P=0.001
No Relapses
PS-adj. HR: 0.38
P=0.003
Over 24 months*
65.4
87.3
52.9
32.2
46.7
78.9
31.5
13.6 0
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=3.03
P<0.0001
“Hit Hard and Early”: Natalizumab Stabilises the Disease (Phase 3 and STRATA Studies)
2.36
2.69 2.54
3.13 3.07 3.22 3.24 3.21 3.15 3.17
2.38 2.36 2.39
2.90 2.69 2.72
2.84 2.85 2.79 2.92
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
FeederStudy
Baseline
FeederStudyEnd
Safety Study End†
STRATABaseline
STRATA48 Weeks
STRATA96
Weeks
STRATA144
Weeks
STRATA192
Weeks
STRATA240
Weeks
STRATA288
Weeks
1 Year 2 Years 3 Years 4 Years 5 Years
Cessation/
Treatment Gap* Original Placebo
Original Natalizumab
Original Placebo – Now on Natalizumab
Me
an
ED
SS
Sc
ore
n = 380 707 381 707 280 552 385 709 274 569 230 479 205 463 194 427 178 410 150 345
*P<0.0001; †includes data on patients dosed with natalizumab.
Rudick R et al. Presented at ECTRIMS; October 2-5, 2013; Copenhagen, Denmark. P593.
6 Years
Real-World Use: At Population Level, Natalizumab Stabilises the Disease Regardless of Disability Level
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
0 6 12 18 24 30 36 42 48
Med
ian
ED
SS
Sco
re
Time (months)
Kappos L et al. Presented at ENS; June 9–12, 2012; Prague, Czech Republic. O261.
Baseline EDSS Score ≤3.0 (n=1591)
Baseline EDSS Score >3.0 (n=1840)
Natalizumab should be used according to the SmPC
Tysabri Observational Program (TOP)
TOP 5-Year Interim Analysis: EDSS Improvement vs Progression
Disability in Overall Population
Years*
n
Mean (SD)
EDSS scores
0 4797 3.5 (1.6)
1 2064 3.3 (1.8)
2 1304 3.3 (1.8)
3 744 3.3 (1.8)
4 325 3.3 (1.9)
*Years of observation where values for year 0 are those at baseline. EDSS progression was defined as an increase, sustained for 6 months, of
≥0.5 points from a baseline EDSS score ≥6.0, of ≥1.0 point from a baseline EDSS score of ≥1.0 to <6.0, or of ≥1.5 points from a baseline EDSS
score of 0. EDSS improvement was evaluated in patients with EDSS scores ≥2.0 at baseline and was defined as a decrease of ≥1.0 point from
baseline EDSS score sustained for 6 months. SD=standard deviation; CI=confidence interval.
Butzkueven H. et al. J Neurol Neurosurg Psychiatry. 2014; Feb 14. [Epub ahead of print].
Probability of confirmed EDSS improvement was significantly greater than the probability of
confirmed worsening (P<0.0001)
Alemtuzumab Also Stabilises Disease over Short Term at Population Level
1. Giovannoni G et al. Presented at AAN; March 16–23, 2013; San Diego, CA. P07.120; 2. Coles AJ et al. Lancet. 2012;380:1829-1839.
Mean EDSS: Change from Baseline in CARE MS II
Mean
ED
SS
Sco
re
Follow-up (months)
SC IFNβ-1a 44 µg Alemtuzumab 12 mg
0.24 increase
P=0.0064
0.17 decrease
P=0.0044
0 3 6 9 12 15 18 21 24
3.0
2.0
1.0
0
4.0
Negative* Anti-JCV
antibody status 0.1/1000
Treatment exposure time or prior IS use does not impact
the risk estimates as long as the patient remains
JCV Ab negative
Data beyond 4 years of treatment are limited.
*Based on natalizumab exposure and 285 confirmed PML cases as of September 5, 2012. Prior IS data in overall
natalizumab-treated patients based on proportion of patients with IS use prior to natalizumab therapy in TYGRIS as of May
2011 and prior IS data in PML patients as of September 5, 2012. The analysis assumes that 55% of natalizumab-treated MS
patients were anti-JCV antibody-positive and that all PML patients test positive for anti-JCV antibodies prior to the onset and
diagnosis of PML. The estimate of PML incidence in anti-JCV antibody-negative patients is based on the assumption that all
patients received at least 1 dose of natalizumab. Assuming that all patients received at least 18 doses of natalizumab, the
estimate of PML incidence in anti-JCV antibody-negative patients was generally consistent (0.1/1000; 95% CI 0.00–0.62).
In Anti-JCV Ab− Patients, Risk of PML Remains Constant Irrespective of Exposure Time or Prior IS Use
IS=immunosuppressant; PML=progressive multifocal leukoencephalopathy.
http://multiple-sclerosis-research.blogspot.co.uk/2014/01/clinic-speak-what-is-high-pml-risk.html. Accessed February 21, 2014.
Natalizumab should be used according to the SmPC
Anti-JCV Ab Status and Weighing Risk of Disease vs Risks
and Benefits of Treatment: AFFIRM
D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D
D Patients with increase in disability 170
Patients with at least 1 relapse 280
Patients with hypersensitivity reactions 40
Patients with no significant harm 680
1000 patients without natalizumab
290
540
0
460
Polman CH et al. N Engl J Med. 2006;354:899-910; Bloomgren G et al. N Engl J Med. 2012;366:1870-80.
Adapted after Wolfgang Gaissmaier, with thanks.
1000 patients with natalizumab, anti-JCV− D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D
D D D D D D D D D D
D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D
D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D
D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D
D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D
Natalizumab should be used according to the SmPC
Anti JCV Ab Status and Weighing Risk of Disease vs Risks
and Benefits of Treatment: AFFIRM
D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D
D Patients with increase in disability 170
Patients with at least 1 relapse 280
Patients with hypersensitivity reactions 40
Patients developing PML in following 2 years 5
Patients with no significant harm 675
290
540
0
0
460
D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D
D D D D D D D D D D
D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D
D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D
D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D
D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D
Polman CH et al. N Engl J Med. 2006;354:899-910; Bloomgren G et al. N Engl J Med. 2012;366:1870-80.
Adapted after Wolfgang Gaissmaier, with thanks.
1000 patients without natalizumab 1000 patients with natalizumab, anti-JCV+
Natalizumab should be used according to the SmPC
Patient Leaflet Allowing Shared Decision Making
http://multiple-sclerosis-research.blogspot.co.uk/2014/01/clinic-speak-what-is-high-pml-risk.html. Accessed February 21, 2014;
Plavina T et al. Presented at CMSC; May 29–June 1, 2013; Orlando, FL. Poster DX.51.
What is your risk of
developing PML?
What is
your
JC virus
status?
RISK FACTOR:
Previous treatment with
immunosuppressive (IS) drugs.
These are drugs that reduce the
activity of your body’s immune
system.
RISK FACTOR:
TYSABRI treatment
duration, especially
over 2 years.
Positive
Negative
Have you previously taken
immunosuppressants?
No
Yes
How long have you
been on TYSABRI?
49−72 months
25−48 months
1−24 months
Low PML risk High PML risk
>1.5
1 in 10,000
1 in 1000
≤0.9
≤1.1
≤1.3
≤1.5
Ab level
How long have you
been on TYSABRI?
49−72 months
25−48 months
1−24 months
1 in 89
1 in 556
Insufficient data
1 in 10,000
≤1.1
≤1.3
≤1.5
1 in 2500
1 in 1429
1 in 833
1 in 769
1 in 118
≤0.9
>1.5
Ab level
≤1.1
≤1.3
≤1.5
1 in 3333
1 in 1429
1 in 1000
1 in 833
1 in 123
≤0.9
>1.5
Ab level
RISK FACTOR:
Ab level is the level of
anti-JCV antibodies in
your blood.
Natalizumab should be used according to the SmPC
Discussing Risk of Therapies with Patients: How Willing Are Patients to Accept Risk ?
Heesen C et al. Mult Scler. 2010;16:1507-1512.
Putative PML Risk Making Patients and Physicians Stop Natalizumab
Neurologist should discuss concerns about MS and risk of treatment with each
patient in order to tailor the treatment decision to each patient’s concerns
0
20
40
60
80
100
1/100,000 2/10,000 1/100 1/10
Pers
on
s (
%)
Physicians (n=66)
Patients (n=69)
Patients are willing
to accept a higher
risk of PML
than neurologists
Value of PML Risk Stratification
• Anti-JCV antibody-based PML risk stratification has enabled physicians and MS patients to make informed treatment decisions
• Anti-JCV antibody status is the number one factor for PML risk stratification
• Anti-JCV antibody testing is widely utilised in clinical practice
– Unilabs in 2011: 32,108 tests
– Unilabs in 2012: 45,709 (31,812 tests in new patients)
Biogen Idec, data on file.
T2T - NEDA
Zero
tolerance
Natalizumab and Alemtuzumab Are Changing Treatment Objectives in Relapsing MS
Freedom from
disease activity/
disease activity
free
Reduced ongoing
damage
Treat Early
T2T=treat-to-target; NEDA=no evidence of disease activity; CNS=central nervous system.
Holmén C et al. Mult Scler. 2011;17:708-719; Rudick RA et al. Ann Neurol. 2007;62:335-346; Havrdova E et al. Lancet Neurol. 2009;8:254-260;
Gunnarsson M et al. Ann Neurol. 2011;69:83-89; Cohen JA et al. Lancet. 2012;380:1819-1828; Hartung HP et al. Presented at AAN;
March 16–23, 2013; San Diego, CA. P07.093; Phillips J et al. Mult Scler. 2011;17:970-979; Butzkueven H et al. J Neurol Neurosurg Psychiatry.
2014 February. [Epub ahead of print].
T2T - NEDA
Zero
tolerance
Natalizumab and Alemtuzumab Are Changing Treatment Objectives in Relapsing MS
Freedom from
disease activity/
disease activity
free
Reduced ongoing
damage
Potential for CNS
repair
Maintain reserve
capacity
Treat Early
T2T=treat-to-target; NEDA=no evidence of disease activity; CNS=central nervous system.
Holmén C et al. Mult Scler. 2011;17:708-719; Rudick RA et al. Ann Neurol. 2007;62:335-346; Havrdova E et al. Lancet Neurol. 2009;8:254-260;
Gunnarsson M et al. Ann Neurol. 2011;69:83-89; Cohen JA et al. Lancet. 2012;380:1819-1828; Hartung HP et al. Presented at AAN;
March 16–23, 2013; San Diego, CA. P07.093; Phillips J et al. Mult Scler. 2011;17:970-979; Butzkueven H et al. J Neurol Neurosurg Psychiatry.
2014 February. [Epub ahead of print].
T2T - NEDA
Zero
tolerance
Natalizumab and Alemtuzumab Are Changing Treatment Objectives in Relapsing MS
Freedom from
disease activity/
disease activity
free
Reduced ongoing
damage
Potential for CNS
repair
Maintain reserve
capacity
Functional
improvement
Healthy
aging
Treat Early
T2T=treat-to-target; NEDA=no evidence of disease activity; CNS=central nervous system.
Holmén C et al. Mult Scler. 2011;17:708-719; Rudick RA et al. Ann Neurol. 2007;62:335-346; Havrdova E et al. Lancet Neurol. 2009;8:254-260;
Gunnarsson M et al. Ann Neurol. 2011;69:83-89; Cohen JA et al. Lancet. 2012;380:1819-1828; Hartung HP et al. Presented at AAN;
March 16–23, 2013; San Diego, CA. P07.093; Phillips J et al. Mult Scler. 2011;17:970-979; Butzkueven H et al. J Neurol Neurosurg Psychiatry.
2014 February. [Epub ahead of print].
T2T - NEDA
Zero
tolerance
Natalizumab and Alemtuzumab Are Changing Treatment Objectives in Relapsing MS
Freedom from
disease activity/
disease activity
free
Reduced ongoing
damage
Potential for CNS
repair
Maintain reserve
capacity
Functional
improvement
Healthy
aging
Maintain or Improve Quality of Life
Treat Early
T2T=treat-to-target; NEDA=no evidence of disease activity; CNS=central nervous system.
Holmén C et al. Mult Scler. 2011;17:708-719; Rudick RA et al. Ann Neurol. 2007;62:335-346; Havrdova E et al. Lancet Neurol. 2009;8:254-260;
Gunnarsson M et al. Ann Neurol. 2011;69:83-89; Cohen JA et al. Lancet. 2012;380:1819-1828; Hartung HP et al. Presented at AAN;
March 16–23, 2013; San Diego, CA. P07.093; Phillips J et al. Mult Scler. 2011;17:970-979; Butzkueven H et al. J Neurol Neurosurg Psychiatry.
2014 February. [Epub ahead of print].
Survival Analysis
“Escalate early”
MS is an autoimmune
disease hypothesis
15–20 year
experiment
What Is Your Treatment Philosophy? Start Early, Develop Shared Goals, and “Treat for Response”
18 15
51
70
0
20
40
60
80
100
Year 0–1 Year 1–2
Pe
rce
nta
ge
of
Pa
tie
nts
(%
)
Placebo Natalizumab
Overall at 2 years: 37% natalizumab vs 7% placebo (P<0.0001)
Havrdová E. et al. Lancet Neurol. 2009;8:254-226.
Natalizumab and Freedom from Disease Activity/ Disease Activity Free (AFFIRM)
Freedom from Disease Activity/Disease Activity Free: Post hoc analysis of patients with no relapses, no sustained (12-week) disability
progression, no Gd+ lesions, no new or enlarging T2-hyperintense lesions
Non-Highly Active Disease <2 relapses in past 12 months or
no Gd+ lesions at study entry
3 4
34
65
0
20
40
60
80
100
Year 0–1 Year 1–2
Pe
rce
nta
ge
of
Pa
tie
nts
(%
)
n=248 n=458 n=228 n=407 n=59 n=146 n=56 n=137
P<0.0001 P<0.0001 P<0.0001 P<0.0001
Highly Active Disease ≥2 relapses in past 12 months and
≥1 Gd+ lesion at study entry
Managing to the Goals of Therapy
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,
terflunomide, DMF=3-6 months
• Glatiramer acetate=9 months
• Alemtuzumab=24 months
DMF=dimethyl fumarate.
Managing to the Goals of Therapy
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,
terflunomide, DMF=3-6 months
• Glatiramer acetate=9 months
• Alemtuzumab=24 months
“Treat early”
DMF=dimethyl fumarate.
Managing to the Goals of Therapy
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,
terflunomide, DMF=3-6 months
• Glatiramer acetate=9 months
• Alemtuzumab=24 months
“Treat early”
“Choose treatments
individually”
DMF=dimethyl fumarate.
Managing to the Goals of Therapy
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,
terflunomide, DMF=3-6 months
• Glatiramer acetate=9 months
• Alemtuzumab=24 months
“Treat early”
“Choose treatments
individually”
“Monitor vigilantly”
DMF=dimethyl fumarate.
Managing to the Goals of Therapy
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,
terflunomide, DMF=3-6 months
• Glatiramer acetate=9 months
• Alemtuzumab=24 months
“Treat early”
“Choose treatments
individually”
“Monitor vigilantly”
“Switch confidently” DMF=dimethyl fumarate.
Key Takeaways
• We are entering a new era of personalised medicine – Risk of disease being weighed against benefit and risk of treatment
• Treatment goals changing? – Should we adopt treat-to-target from our rheumatology colleagues?
– NEDA, TTT, and DAF have entered the neurology lexicon
– Rebaselining will need to be agent specific
• What is your treatment philosophy? – Escalation (treat for response)
– Induction (treat for response)
• How will you monitor for treatment response? – Incorporate MRI and rebaseline?
• Risk stratification for PML and shared decision making – “Hit hard and early” is an important choice
TTT=treat to target (T2T); DAF=disease activity free.