Assessing Risk Tolerance to DMTs: Understanding and ... · Assessing Risk Tolerance to DMTs:...
Transcript of Assessing Risk Tolerance to DMTs: Understanding and ... · Assessing Risk Tolerance to DMTs:...
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Assessing Risk Tolerance to DMTs:Understanding and Educating About Safety
Assessing Risk Tolerance to DMTs:Understanding and Educating About Safety
Benjamin Greenberg, M.D., M.H.S.UT Southwestern and Childrens Medical Center
Dallas, TexasCMSC 2014
ObjectivesObjectives
In a world of increasing numbers of disease modifying therapies, each with unique mechanisms of actions, relative efficacy, relative risk and safety concerns, how should clinicians counsel patients?
What are your obligations relative to safety education and monitoring of patients?
Are you responsible when patients suffer from rare unexpected complications?
In a world of increasing numbers of disease modifying therapies, each with unique mechanisms of actions, relative efficacy, relative risk and safety concerns, how should clinicians counsel patients?
What are your obligations relative to safety education and monitoring of patients?
Are you responsible when patients suffer from rare unexpected complications?
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Example Package InsertExample Package Insert
Vascular events, including ischemic and hemorrhagic strokes, and peripheral arterial occlusive disease were reported in premarketing clinical trials in patients who received XXX doses (Y-YY) higher than recommended for use in MS. Similar events have been reported with XXX in the post-marketing setting although a casual relationship has not been established.
Cases of lymphoma (cutaneous T-cell lymphoproliferative disorders or diffuse B-cell lymphoma) were reported in premarketing clinical trials in MS patients receiving XXX at, or above, the recommended dose of Y, based on the small number of cases and short duration of exposure, the relationship to XXX remains uncertain.
Vascular events, including ischemic and hemorrhagic strokes, and peripheral arterial occlusive disease were reported in premarketing clinical trials in patients who received XXX doses (Y-YY) higher than recommended for use in MS. Similar events have been reported with XXX in the post-marketing setting although a casual relationship has not been established.
Cases of lymphoma (cutaneous T-cell lymphoproliferative disorders or diffuse B-cell lymphoma) were reported in premarketing clinical trials in MS patients receiving XXX at, or above, the recommended dose of Y, based on the small number of cases and short duration of exposure, the relationship to XXX remains uncertain.
AgendaAgenda
9:00 to 9:45 Introduction to DMTs
Benjamin Greenberg, MD, MHS
9:45 to 10:30 Quantifying Relative Risk of DMTs
Donna Graves, MD
10:30 to 10:45 Break
10:45 to 11:30 Medico-Legal Obligations
Neal Flagg, JD
11:30 to 12:00 Case Examples/Discussion
9:00 to 9:45 Introduction to DMTs
Benjamin Greenberg, MD, MHS
9:45 to 10:30 Quantifying Relative Risk of DMTs
Donna Graves, MD
10:30 to 10:45 Break
10:45 to 11:30 Medico-Legal Obligations
Neal Flagg, JD
11:30 to 12:00 Case Examples/Discussion
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The Past, Present and Future of Disease Modifying Therapies in Multiple SclerosisThe Past, Present and Future of Disease Modifying Therapies in Multiple Sclerosis
Benjamin Greenberg, M.D., M.H.S.Director, Transverse Myelitis and Neuromyelitis Optica Program
Director, Pediatric Demyelinating Disease ProgramUT Southwestern
Childrens Medical CenterDallas, TexasCMSC 2014
Multiple Sclerosis Throughout HistoryMultiple Sclerosis Throughout History
1868 – Jean-Martin Charcot describes in detail, clinical multiple sclerosis and relates it to white matter lesions.
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Suggested Causes of Multiple Sclerosis Throughout History
Suggested Causes of Multiple Sclerosis Throughout History
1900 20001940 1960
Lack of Sweat
Toxic Exposure
Poor Circulation Allergic Reaction Autoimmunereaction against
myelin
Bedrest
Purgatives
Vasodilators Vitamins/Anti-histamines
Immunomodulators
Where it all began……Where it all began……
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FDA Approval of Multiple Sclerosis Therapies
FDA Approval of Multiple Sclerosis Therapies
1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
Interferon Beta-1b (Betaseron)
Interferon Beta-1a (Avonex)
Glatiramer Acetate (Copaxone)
Mitoxantrone (Novantrone)
Interferon Beta-1a (Rebif)
Natalizumab (Tysabri)
Fingolimod (Gilenya)
Teriflunomide (Aubagio)
Tecfidera (BG0012)
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Disease Modifying Therapy in MSDisease Modifying Therapy in MS
PresentPresent
Interferon β 1a
Interferon β 1a
Interferon β 1b
Glatiramer Acetate
Natalizumab
Mitoxantrone
Fingolimod
Teriflunomide
BG-00012
Interferon β 1a
Interferon β 1a
Interferon β 1b
Glatiramer Acetate
Natalizumab
Mitoxantrone
Fingolimod
Teriflunomide
BG-00012
Future (Current Phase II/III)Future (Current Phase II/III)
Alemtuzumab
Daclizumab
Laquinimod
Ocrelizumab
Estradiol
Abatacept
Glatiramer Acetate
Interferon β 1a
Alemtuzumab
Daclizumab
Laquinimod
Ocrelizumab
Estradiol
Abatacept
Glatiramer Acetate
Interferon β 1a
The Complicated Current Therapeutic Climate of Multiple Sclerosis
The Complicated Current Therapeutic Climate of Multiple Sclerosis
Changing diagnostic criteria
Lack of consensus definition of what success in MS means
Lack of consensus on appropriate ‘risk’ taking in MS therapeutics.
Lack of reliable biomarkers that predict outcome, guide therapy selection or confirm response to therapy.
A complete lack of agents for progressive disease
Changing diagnostic criteria
Lack of consensus definition of what success in MS means
Lack of consensus on appropriate ‘risk’ taking in MS therapeutics.
Lack of reliable biomarkers that predict outcome, guide therapy selection or confirm response to therapy.
A complete lack of agents for progressive disease
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The Impact of Increased Diagnostic Sensitivity Relative to Outcomes
The Impact of Increased Diagnostic Sensitivity Relative to Outcomes
Clin
ical
Eve
nts
The Impact of Increased Diagnostic Sensitivity Relative to Outcomes
The Impact of Increased Diagnostic Sensitivity Relative to Outcomes
Clin
ical
Eve
nts
Poser Criteria for Separation in Space and Time
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The Impact of Increased Diagnostic Sensitivity Relative to Outcomes
The Impact of Increased Diagnostic Sensitivity Relative to Outcomes
Clin
ical
Eve
nts
MR
I E
vent
s
Transition to 2005 McDonald Criteria
Transition to 2010 McDonaldCriteria
The Impact of Increased Diagnostic Sensitivity Relative to Outcomes
The Impact of Increased Diagnostic Sensitivity Relative to Outcomes
Clin
ical
Eve
nts
25% of cases diagnosed with MS at Autopsyare undiagnosed in life
Acta Neurol Scand. 1989 May 79(5):428-30
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The Impact of Increased Diagnostic Sensitivity Relative to Outcomes
The Impact of Increased Diagnostic Sensitivity Relative to Outcomes
Clin
ical
Eve
nts
25% of cases diagnosed with MS at Autopsyare undiagnosed in life
Acta Neurol Scand. 1989 May 79(5):428-30
The Impact of Increased Diagnostic Sensitivity Relative to Outcomes
The Impact of Increased Diagnostic Sensitivity Relative to Outcomes
Clin
ical
Eve
nts
25% of cases diagnosed with MS at Autopsyare undiagnosed in life
Acta Neurol Scand. 1989 May 79(5):428-30
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The Impact of Increased Diagnostic Sensitivity Relative to Outcomes
The Impact of Increased Diagnostic Sensitivity Relative to Outcomes
Clin
ical
Eve
nts
25% of cases diagnosed with MS at Autopsyare undiagnosed in life
Acta Neurol Scand. 1989 May 79(5):428-30
The Impact of Increased Diagnostic Sensitivity Relative to Outcomes
The Impact of Increased Diagnostic Sensitivity Relative to Outcomes
Clin
ica
l Eve
nts
MR
I E
ven
tsIn
flam
mat
ion
Atr
op
hy
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HOW SHOULD WE JUDGE SUCCESS IN MS?
HOW SHOULD WE JUDGE SUCCESS IN MS?
We All Have an Internal Barometer of Concern
We All Have an Internal Barometer of Concern
Is the therapy working?
“Disability”
MRI
Relapses
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Success is not Defined in a VacuumSuccess is not Defined in a VacuumMaintain Therapy
Change Therapy
Success is not Defined in a VacuumSuccess is not Defined in a VacuumMaintain Therapy
Change Therapy
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MEASURES OF SUCCESS:REVIEW OF THE DATA
MEASURES OF SUCCESS:REVIEW OF THE DATA
How Do We Define Success in Treating Multiple Sclerosis
How Do We Define Success in Treating Multiple Sclerosis
Stable MRI
Lack of Relapses
Lack of new changes in walking, vision or sensation
Lack of changes in cognition
Improvement in symptoms
Stable MRI
Lack of Relapses
Lack of new changes in walking, vision or sensation
Lack of changes in cognition
Improvement in symptoms
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Betaseron™/Extavia™ Avonex™ Copaxone™ Rebif ™
FDA Approval 1993 1996 1996 2002
Route SC IM SC SC
Frequency QOD Weekly Daily 3x week
Reduction in Relapses
31% 32% 29% 32%
FDA Approved Injectable Therapies in RRMSFDA Approved Injectable Therapies in RRMS
Number of Patients at Risk
PlaceboNatalizumab
315 257 229 204 182 164 154 141 133 129
627 577 542 515 487 464 447 436 424 418
Pro
bab
ility
of
Rel
apse
0.00.1
0.2
0.4
0.60.7
Weeks0 24
P < .0001
Placebo 56%
Natalizumab 28%
HR = 0.41 (CI: 0.33–0.51)
72 96 104
0.3
0.5
4812 36 60 84
Natalizumab Risk of Relapse Over 2 Years
Natalizumab Risk of Relapse Over 2 Years
NEJM, March 2, 2006
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Pro
po
rtio
n W
ith
Su
sta
ine
d P
rog
res
sio
n
Hazard ratio (HR) = 0.58 (95% CI: 0.43–0.77)P =
.0002Placebo
29%
Natalizumab 17%
0.0
0.1
0.2
0.3
0.4
Weeks0 12 24 36 48 60 72 84 96 108 120
Number of Patients at Risk
Placebo
Natalizumab
315 296 283 264 248 240 229 216 208 200
627 601 582 567 546 525 517 503 490 478
199
473
Sustained Disability Progression with Natalizumab
Sustained Disability Progression with Natalizumab
NEJM, March 2, 2006
Outcome Measures For FingolimodOutcome Measures For Fingolimod
Outcome Placebo Fingolimod0.5 mg
Fingolimod1.25 mg
P Value
Annualized Relapse Rate 0.40 0.18 0.16 <0.001
Patients without a 6 month sustained change in EDSS
75.9% 87.5% 88.5% 0.01
Mean Number of Gd Enhancing Lesions at 24
months
1.1 0.2 0.2 <0.001
Mean Number of new or enlarged T2 lesions
9.8 2.5 2.5 <0.001
Change in brain volume over 24 months
-1.31 -0.84 -0.89 <0.001
NEJM, 2010, 362:387-401
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Outcome Measures For FingolimodOutcome Measures For Fingolimod
Outcome Interferonbeta 1a
(IM)
Fingolimod0.5 mg
Fingolimod1.25 mg
P Value
Annualized Relapse Rate 0.33 0.16 0.20 <0.001
Patients with Zero Relapses 70.1% 82.5% 80.5% 0.01
Mean Number of Gd Enhancing Lesions at 24
months
0.51 0.23 0.14 <0.001
Mean Number of new or enlarged T2 lesions
2.6 1.7 1.5 <0.001
Change in brain volume over 24 months
-0.45 -0.31 -0.30 <0.001
NEJM, 2010, 362:402-415
Outcome Measures For TeriflunomideOutcome Measures For Teriflunomide
Outcome Placebo Teriflunomide7 mg daily
Teriflunomide14 mg daily
P Value
Mean Number of New Gd Enhancing Lesions
2.25 0.17 0.17 <0.02
Mean Number of new or enlarged T2 lesions
1.52 0.41 0.71 <0.03
Neurology, 2006, 66:894-900
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Teriflunomide: Phase III TOWER Study
Teriflunomide: Phase III TOWER Study
Kappos L, et al. Presented at ECTRIMS 2012; October 9–13, 2012; Lyon, France. [Abstract 153]
Primary Endpoint: ARR
RRR: 22.3%P = 0.0183
RRR: 36.3%P = 0.0001
TOWER: Secondary Efficacy OutcomesTOWER: Secondary Efficacy Outcomes
Secondary Endpoint Placebo Teri 7 mg Teri 14 mg
Patients free from relapse37.7% 55.4* 51.5*
Time to 12-week confirmed disability progressionHR vs placebo
0.955 0.685*
Mean change from baseline EDSS to week 48 0.089 0.042 -0.05*
Mean change from baseline FIS to week 48 4.7 2.5 1.9
Mean change from baseline SF-36 scores to week 48
PhysicalMental
-1.082-2.913
-0.396-2.031
-0.105-1.434
*Statistically significant vs placebo.FIS = Fatigue Impact Scale; SF-36 = Short Form 36 questionnaireKappos L, et al. Presented at ECTRIMS 2012; October 9–13, 2012; Lyon, France. [Abstract 153]
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Outcome Measures For Dimethyl Fumarate
Outcome Measures For Dimethyl Fumarate
Outcome Placebo BG00012120 mg daily
BG00012120 mg tid
BG00012240 mg
tid
P Value
Mean Number of New Gd Lesions
weeks 12-24
4.5 3.3 3.1 1.4 <0.0001
Number of patients with no new T2
lesions at week 24
26% 27% 27% 63% 0.0006
ARR Weeks 0-24
0.65 0.42 0.78 0.44 0.272
ARRWeeks 25-48
0.26 0.24 0.47 0.16
Lancet, 2008, 372:1463-72
Dimethyl Fumarate Pooled Efficacy Analysis of
DEFINE and CONFIRM
Dimethyl Fumarate Pooled Efficacy Analysis of
DEFINE and CONFIRMEndpoint (at 2 years) Placebo BG-12 BID
ARRReduction vs placebo
0.371 0.191*49%
Time to 12-week confirmed disability progressionHR vs placebo
0.68*
Time to 24-week confirmed disability progressionHR vs placebo
0.71*
Mean number of Gd-enhancing lesionsReduction vs placebo
1.9 0.3*83%
Mean number of new or enlarging T2 lesionsReduction vs placebo
16.8 3.7*78%
Mean number of new T1 hypointense lesionsReduction vs placebo
6.3 2.2*65%
*Statistically significant vs placebo.Gold R, et al. Presented at ECTRIMS 2012; October 9–13, 2012; Lyon, France. [Abstract 151]
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Annualized Relapse Rates From Pivotal Clinical Trials
Annualized Relapse Rates From Pivotal Clinical Trials
IFNB Multiple Sclerosis Study Group (1993) Interferon beta-lb is effective in relapsing-remitting multiple sclerosis. Neurology: 655–661; Jacobs LD, Cookfair DL, Rudick R a, Herndon RM, Richert JR, et al. (1996) Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Annals of neurology 39: 285–294 ; Johnson KP, Brooks BR,
Cohen JA, Ford CC, Goldstein J, et al. (1995) Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer Multiple Sclerosis Study Group. Neurology 45: 1268–1276 ; PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group (1998)
Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Lancet 352: 1498–1504 ; Polman CH, O Connor PW, Havrdova E, Hutchinson M, Kappos L, et al. (2006) A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. New England Journal of Medicine 354: 899. ; O'Connor P, Wolinsky JS, Confavreux C, Comi G, Kappos L, et al. (2011) Randomized trial of oral teriflunomide for relapsing multiple sclerosis. The New England journal
of medicine 365: 1293–1303 ; Kappos L, Radue EW, O’Connor P, Polman C, Hohlfeld R, et al. . (2010) A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. New England Journal of Medicine: 387–401. ; Gold R, Kappos L, Bar-Or A, Arnold D, Giovannoni G, et al. . (2011) Clinical efficacy of BG-12, an oral therapy, in relapsing-remitting multiple sclerosis: data from the phase 3 DEFINE trial. In: ECTRIMS.
Amsterdam ; Comi G, Jeffery D, Kappos L, Montalban X, Boyko A, et al. (2012) Placebo-controlled trial of oral laquinimod for multiple sclerosis. The New England journal of medicine 366: 1000–1009
The Ins and Outs of Annualized Relapse Rate
The Ins and Outs of Annualized Relapse Rate
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The Ins and Outs of Annualized Relapse Rate
The Ins and Outs of Annualized Relapse Rate
PlaceboTreated
The Ins and Outs of Annualized Relapse Rate
The Ins and Outs of Annualized Relapse Rate
Treated Placebo
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AlemtuzumabAlemtuzumab
“Campath”, developed in the Cambridge Pathology Department
Humanized monoclonal antibody targeting CD52
FDA approved for treatment of B-cell CLL
CD52 is expressed on lymphocytes, natural killer cells, dendritic cells and macrophages.
“Campath”, developed in the Cambridge Pathology Department
Humanized monoclonal antibody targeting CD52
FDA approved for treatment of B-cell CLL
CD52 is expressed on lymphocytes, natural killer cells, dendritic cells and macrophages.
Biologic Effect of AlemtuzemabBiologic Effect of Alemtuzemab
Induces apoptosis of lymphocytes and NK cells.
Subsequent reconstitution of the immune system with relative overexpression of Treg cells and naïve B cells.
Induces apoptosis of lymphocytes and NK cells.
Subsequent reconstitution of the immune system with relative overexpression of Treg cells and naïve B cells.
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Alemtuzumab Phase II TrialAlemtuzumab Phase II Trial
334 Randomized
111
Interferon beta1a
(SC 3x/wk)
113
12 mg Alemtuzumab
108 Received first cycle
102 Received second cycle
24 Received
third cycle
110
24 mg Alemtuzumab
108 Received first cycle
105 Received second cycle
22 Received
third cycle
December 2002 July 2004 September 2004 September 2005
Enrollment Begins Last PatientRandomizes
Last PatientDosed
AlemtuzumabDosing
Suspended
NEJM, 2008, 359(17):1786-801)
Outcome Measures For AlemtuzumabOutcome Measures For Alemtuzumab
Outcome Interferon Alemtuzumab(Combined Doses)
P Value
Annualized Relapse Rate 0.36 0.10 <0.001
Change in Mean EDSS from Baseline 0.38 -0.39 <0.001
EDSS Score Improvement 33.7% 57.2% <0.001
Sustained Disability for 6 months 26.2% 9.0% <0.001
Patients with No Relapse 51.6% 80.2% <0.001
NEJM, 2008, 359(17):1786-801)
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Adverse Events and Safety for Alemtuzumab
Adverse Events and Safety for Alemtuzumab
Event Interferon Alemtuzumab12 mg Dose
Alemtuzumab24 mg dose
Serious SAE 22.4 22.2 25.0
Liver Toxicity 15% 1.9% 2.8%
Serious Infection 1.9% 2.8% 5.6%
URI 27.1% 44.4% 50.9%
HSV 2.8% 8.3% 8.3%
Thyroid Changes 2.8% 25.9% 19.4%
Serious Hyperthyroidism
0 0.9% 1.9%
ITP 0.9% 1.9% 3.7%
Cancer 0.9% 0 2.8%
Death 0 0.9% 0.9%
NEJM, 2008, 359(17):1786-801)
Figure 2 Efficacy outcomes through month 60 and complete follow-up (A) Kaplan-Meier estimates of time to sustained accumulation of disability through complete follow-up with the
number of at-risk patients listed below.
Coles A et al. Neurology 2012;78:1069-1078
© 2013 American Academy of Neurology
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Figure 3: Proportion of patients with infections and first autoimmune event (A) Proportion of patients with infections.
Coles A et al. Neurology 2012;78:1069-1078
© 2013 American Academy of Neurology
Phase III Alemtuzumab TrialsCARE-MS II
Patients Who Failed Prior Therapy
Phase III Alemtuzumab TrialsCARE-MS II
Patients Who Failed Prior Therapy
202 (87%) of 231 patients randomly allocated interferon beta 1a and 426 (98%) of 436 patients randomly allocated alemtuzumab 12 mg were included in the primary analyses.
104 (51%) patients in the interferon beta 1a group relapsed (201 events) compared with 147 (35%) patients in the alemtuzumab group (236 events; rate ratio 0·51 [95% CI 0·39—0·65]; p<0·0001), corresponding to a 49·4% improvement with alemtuzumab.
94 (47%) patients in the interferon beta 1a group were relapse-free at 2 years compared with 278 (65%) patients in the alemtuzumab group (p<0·0001).
40 (20%) patients in the interferon beta 1a group had sustained accumulation of disability compared with 54 (13%) in the alemtuzumab group (hazard ratio 0·58 [95% CI 0·38—0·87]; p=0·008), corresponding to a 42% improvement in the alemtuzumab group.
202 (87%) of 231 patients randomly allocated interferon beta 1a and 426 (98%) of 436 patients randomly allocated alemtuzumab 12 mg were included in the primary analyses.
104 (51%) patients in the interferon beta 1a group relapsed (201 events) compared with 147 (35%) patients in the alemtuzumab group (236 events; rate ratio 0·51 [95% CI 0·39—0·65]; p<0·0001), corresponding to a 49·4% improvement with alemtuzumab.
94 (47%) patients in the interferon beta 1a group were relapse-free at 2 years compared with 278 (65%) patients in the alemtuzumab group (p<0·0001).
40 (20%) patients in the interferon beta 1a group had sustained accumulation of disability compared with 54 (13%) in the alemtuzumab group (hazard ratio 0·58 [95% CI 0·38—0·87]; p=0·008), corresponding to a 42% improvement in the alemtuzumab group.
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Choosing A TherapyChoosing A Therapy
MS Therapeutics: A Brave New WorldMS Therapeutics: A Brave New World
Safety
Effi
cacy
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MS Therapeutics: A Brave New WorldMS Therapeutics: A Brave New World
Safety
Effi
cacy
MS Therapeutics: A Brave New WorldMS Therapeutics: A Brave New World
Safety
Effi
cacy
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MS Therapeutics: A Brave New WorldMS Therapeutics: A Brave New World
Safety
Effi
cacy
MS Therapeutics: A Brave New WorldMS Therapeutics: A Brave New World
Safety
Effi
cacy
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What is an Acceptable Risk Benefit Ratio?
What is an Acceptable Risk Benefit Ratio?
How do we handle therapies with a risk of death?
How do we handle risk of malignancy?
How do we handle risk of infection?
Defining benefits is based on development of accurate measures/markers.
How do we handle therapies with a risk of death?
How do we handle risk of malignancy?
How do we handle risk of infection?
Defining benefits is based on development of accurate measures/markers.
Improving Therapeutic Choices Improving Therapeutic Choices
Responder Status
Risk of Therapy
Disease Severity
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ConclusionsConclusions
The therapeutic landscape is complicated and getting more complicated
Therapies have to be individualized based on disease severity, risk of disease progression and risk of therapeutic options
Side effect profiles and adherence
A detailed conversation with patients is needed
The therapeutic landscape is complicated and getting more complicated
Therapies have to be individualized based on disease severity, risk of disease progression and risk of therapeutic options
Side effect profiles and adherence
A detailed conversation with patients is needed