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