Benefit Risk from a Healthcare Provider Perspectiive

Disease Management

Holistic Approach: Benefit Risk from HCP & Patient Perspective

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.

http://www.ms-res.org/







How much of my time is taken up with DMTs?

10%

60%

5%

15%

5%

DMTs

Symptomatic

Diagnostic

Admin

Blog

My clinical time

Epstein Bar Virus

Genetics

Vitamin D

Smoking

Risks

Adverse events

Differential Diagnosis

MRI

Evoked Potentials

Lumbar puncture

Blood Tests

Diagnostic Criteria

Cognition

Depression

Fatigue

Bladder

Bowel

Sexual dysfunction Tremor

Pain Swallowing

Spasticity Falls

Balance problems Insomnia

Restless legs Fertility

Clinical trials

Gait

Pressure sores

Oscillopsia

Emotional lability

Seizures

Gastrostomy

Rehab

Suprapubic catheter Intrathecal

baclofen

Physio- therapy

Speech therapy

Occupational Therapy

Functional neurosurgery

Colostomy

Tendonotomy

Studying

Employment Relationships

Travel

Vaccination

Anxiety

Driving

Nurse specialists

Family counselling

Relapses

1st line

2nd line

Maintenance Escalation Induction

Monitoring

Disease-free

Disease progression

DMTs

Side Effects

Advanced Directive

Exercise

Diet

Alternative Medicine

Pregnancy Breast Feeding

Research

Insurance

Visual loss

Palliative Care

Assisted suicide

Social services

Legal aid

Genetic counselling

Prevention

Diagnosis

DMT Symptomatic

Therapist

Terminal

Counselling An holistic approach to MS; beta ver. 3.2

Intrathecal phenol

Fractures

Movement disorders

Osteopaenia

Brain atrophy

Hearing loss

Tinnitus

Photophobia

Hiccoughs

DVLA

Neuroprotection

Psychosis

Depersonaliation

Brain Health

Cognitive Reserve

Sudden death

Suicide

OCD

Narcolepsy

Apnoea Carers

Respite

Hospice

Respite

Dignitas

Advanced Directive

Rhiztomy

Wheelchair

Walking aids

Blood/Organ donation

Brain donation

Exercise therapy

NABs

Autoimmunity

Infections

Outcome measures

Web Resources

Pathogenesis

Double vision

What is MS?

NEDA

T2T OCT

Neurofilaments

JCV status Pharma

Anaesthesia

The hypothetical Ideal

Reliable

long-term efficacy

Maintaining

QOL

Maintaining

independence

Maintaining the

ability to work

No issue for

pregnancy/fertility

Maximum reduction

of MS disease activity

Maximum

tolerability

Maximum

safety

Ease of

use

Minor impact on

everyday life

Risks vs. Benefits

How bad is MS?

MS Infographic

www.ms-res.org

Audience Response Question

What proportion of MSers are unemployed by the time they need a walking aid (EDSS 6.0)?

1. <20%

2. 25-50%

3. 50-60%

4. >60%

> 60%

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

The Gambler’s Dilemma

What about benign MS?


What proportion of MSers have benign MS?

1. >50%

2. 40-50%

3. 30-40%

4. <30%

Hospital-based populations (EDSS < 3.5) • 15 years ~30% • 25 years ~15% • 30 years ~5% • 50 years ~2.5% Community-based populations • 15 years ~45%

163 patients with “benign” MS

(disease duration >15 years and EDSS <3.5):

45% cognitive impairment

49% fatigue

54% depression

What is benign MS?

Impact of MS: cognitive functioning in the CIS stage

Feuillet et al. MSJ 2007

CIS Patients n = 40

57%

7%

-20%

0%

20%

40%

60%

Healthy Controls n = 30

p < 0.0001

Deficits were found mainly in memory, speed of information

processing, attention and executive functioning Patients failing

≥ 2 cognitive tests


Do you believe in the concept of a therapeutic window?

1. Yes

2. No

3. Maybe

Coles et al. J Neurol. 2006 Jan;253(1):98-108.

Post-inflammatory neurodegeneration

Early vs. Late?

Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFN-1b trial

Goodin et al. Neurology 2012;78:1315-1322.

Natalizumab STRATA: stable EDSS scores for up to 5 years

*P<0.0001

Kappos L et al. Presented at ECTRIMS; October 10–13, 2012; Lyon, France P520.

1 Year 2 Years 3 Years 4 Years 5 Years

Cessation/

Treatment Gap* Original Placebo

Original Natalizumab

Original Placebo – Now on Natalizumab

Mean

ED

SS

Sco

re

n = 380 707 381 707 280 552 385 709 274 569 230 479 205 462 194 427 174 393

21

Tur et al. Interferon Beta-1b for the Treatment of Primary Progressive Multiple Sclerosis: Five-Year Clinical Trial Follow-up. Arch Neurol. 2011 Nov;68(11):1421-7.

Therapeutic Lag

Motor system to legs

Cerebellar or balance systems

Bladder Therapeutic window 1

Therapeutic window 2


Upper limbs

Sensory

Cognition

Vision

Etc.





Therapeutic window 8, etc….

Diagnosis of Progressive MS

Effective DMTs could still target the remaining windows of therapeutic opportunity for individual neurological

systems

The Asynchronous Progressive MS hypothesis


Do you believe in the concept of a therapeutic window?

1. Yes

2. No

3. Maybe

No I think there are

multiple windows

17yr female,

diagnosed

with CIS

after

presenting

with myelitis

18yr, 1st year

university

diagnosed

with MS after

having L optic

neuritis

Abnormal MRI; >9

T2 lesions on brain

MRI and spinal cord

lesion at C5

2000 2001

clumsy

left

hand

pins &

needles

in legs

IFN-beta

2002 2003

R optic

neuritis

2004

Bladder dysfunction

Graduate

trainee

marketing

Full

time

employment

Off work

~3 months

of the year

Dec 2007

Brainstem

syndrome;

diplopia

and ataxia

? glatiramer

acetate

Cervical cord

relapse

weak L arm

with pain

High lesion

load with

brain

atrophy

Gd-enhancing

lesion of upper

cervical cord

Splits from

her partner

depression ,

anxiety and fatigue

Reduced mobility

Occupational

health

assessment

natalizumab

New

partner

New job

junior management

position

Residual deficits:

Normal walking 300m, unable to run &

exercise. Intermittent sensory symptoms

in L arm. Mild urinary frequency

Jan 2008

JCV

positive

3-monthly MRI

monitoring

? fingolimod

Oct 2013

Annual MRI

monitoring

JCV

high positive

Final

year of

school

University

Early or late?

26

Mo

nito

rin

g

Tre

atm

ent

Clin

ica

l O

ccu

p &

so

cia

l

17% 85%

>800,000 SlideShare Views

17yr female,

diagnosed

with CIS

after

presenting

with myelitis

18yr, 1st year

university

diagnosed

with MS after

having L optic

neuritis

Abnormal MRI; >9

T2 lesions on brain

MRI and spinal cord

lesion at C5

2000 2001

clumsy

left

hand

pins &

needles

in legs

IFN-beta

2002 2003

R optic

neuritis

2004

Bladder dysfunction

Graduate

trainee

marketing

Full

time

employment

Off work

~3 months

of the year

Dec 2007

Brainstem

syndrome;

diplopia

and ataxia

? glatiramer

acetate

Cervical cord

relapse

weak L arm

with pain

High lesion

load with

brain

atrophy

Gd-enhancing

lesion of upper

cervical cord

Splits from

her partner

depression ,

anxiety and fatigue

Reduced mobility

Occupational

health

assessment

natalizumab

New

partner

New job

junior management

position

Residual deficits:




Jan 2008

JCV

positive

3-monthly MRI

monitoring

? fingolimod

Oct 2013

Annual MRI

monitoring

JCV

high positive

Final

year of

school

University

Early or late?

34

Mo

nito

rin

g

Tre

atm

ent

Clin

ica

l O

ccu

p &

so

cia

l

Redefining our treatment target

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

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

17yr female,

diagnosed

with CIS

after

presenting

with myelitis

18yr, 1st year

university

diagnosed

with MS after

having L optic

neuritis

Abnormal MRI; >9

T2 lesions on brain

MRI and spinal cord

lesion at C5

2000 2001

clumsy

left

hand

pins &

needles

in legs

IFN-beta

2002 2003

R optic

neuritis

2004

Bladder dysfunction

Graduate

trainee

marketing

Full

time

employment

Off work

~3 months

of the year

Dec 2007

Brainstem

syndrome;

diplopia

and ataxia

? glatiramer

acetate

Cervical cord

relapse

weak L arm

with pain

High lesion

load with

brain

atrophy

Gd-enhancing

lesion of upper

cervical cord

Splits from

her partner

depression ,

anxiety and fatigue

Reduced mobility

Occupational

health

assessment

natalizumab

New

partner

New job

junior management

position

Residual deficits:




Jan 2008

JCV

positive

3-monthly MRI

monitoring

? fingolimod

Oct 2013

Annual MRI

monitoring

JCV

high positive

Final

year of

school

University

Early or late?

39

Mo

nito

rin

g

Tre

atm

ent

Clin

ica

l O

ccu

p &

so

cia

l

Dec 2007 Jul 2010 Jul 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

End-organ damage

Rheumatoid arthritis End-stage joint disease

Control Multiple sclerosis

Brain atrophy occurs across all stages of the disease

De Stefano, et al. Neurology 2010

n= 963 MSers

Treatment-effect on atrophy correlates with treatment-effect on disability

Sormani et al. Ann Neurol 2014;75:43–49.

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

Alemtuzumab Improves Brain MRI Outcomes

in Patients With Active Relapsing-Remitting

Multiple Sclerosis: Three-Year Follow-up of the

CARE-MS Studies

Douglas L Arnold,1,2 Elizabeth Fisher,3 Jeffrey A Cohen,4 Frederik Barkhof,5

Krzysztof W Selmaj,6 David H Margolin,7 Jeffrey Palmer,7 Edward J Fox8

AAN 2014

Blitz S65-008

1NeuroRx Research, Montréal, Québec, Canada, and 2Department of Neurology and Neurosurgery, Montreal

Neurological Institute, McGill University, Montreal, Québec, Canada; 3Department of Biomedical Engineering,

Cleveland Clinic, Cleveland, OH, USA; 4Cleveland Clinic, Cleveland, OH, USA; 5VU University Medical Centre,

Amsterdam, Netherlands; 6Department of Neurology, Medical University of Łódź, Łódź, Poland; 7Genzyme, a

Sanofi company, Cambridge, MA, USA; 8University of Texas Medical Branch, Round Rock, TX, USA

CARE-MS I & II Three-Year MRI Outcomes Change in Brain Parenchymal Fraction (BPF)

Alemtuzumab slowed brain volume loss over 3 years, as assessed by change in BPF

For both patient populations, the median percentage reduction in BPF observed in in Year 3 (0.19% and 0.10%, respectively) was smaller than that observed in Year 1 (0.59% and 0.48%) and Year 2 (0.25% and 0.22%)

Percentage Change in BPF in Formerly Treatment-Naive Patients (CARE-MS I)

Percentage Change in BPF in Patients Who Relapsed on Prior Therapy (CARE-MS II)

Me

dia

n C

ha

ng

e F

rom

Ba

se

lin

e, %

(9

5%

CI)

Year No. of Patients 371 367 351 323

% Change from Previous Year – –0.59% –0.25% –0.19%

Me

dia

n C

ha

ng

e F

rom

Ba

se

lin

e, %

(9

5%

CI)

Year 428 414 405 359

– –0.48% –0.22% –0.10%

No. of Patients

% Change from Previous Year

0 1 2 3

-1 .5 0

-1 .2 5

-1 .0 0

-0 .7 5

-0 .5 0

-0 .2 5

0 .0 0

0 1 2 3

-1 .5 0

-1 .2 5

-1 .0 0

-0 .7 5

-0 .5 0

-0 .2 5

0 .0 0

AAN 2014

Blitz S65-008

CARE-MS I & II Three-Year MRI Outcomes Proportion of Patients Free of Gd Lesions, T2 Lesions, and MRI Activity

The majority of alemtuzumab-treated patients were free of MRI activity (absence of Gd-enhancing lesions and new/enlarging T2 hyperintense lesions) at Year 2 and Year 3

MRI activity-free: absence of both Gd-enhancing and new or enlarging T2 hyperintense lesions; CARE-MS=Comparison of

Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis; CI=confidence interval; DMT=disease-modifying therapy; Gd=gadolinium;

MRI=magnetic resonance imaging; Y=year

No. of Patients 359 370 336 356 370 325 354 369 326

Y1 Y2 Y3 Y1 Y2 Y3 Y1 Y2 Y3

Pro

po

rtio

n o

f P

ati

en

ts,

% (

95

% C

I)

0

20

40

60

80

100

Gd-enhancing

lesion-free

New/enlarging

T2 lesion-free

MRI

activity-free

% MRI Activity Free in Treatment-Naive

Patients (CARE-MS I)

% MRI Activity Free in Patients Who

Relapsed on Prior Therapy (CARE-MS II)

No. of Patients 412 421 364 405 423 361

Gd-enhancing

lesion-free

New/enlarging MRI

activity-free

402 414 361

Pro

po

rtio

n o

f P

ati

en

ts,

% (

95

% C

I)

0

20

40

60

80

100

Y1 Y2 Y3 Y1 Y2 Y3 Y1 Y2 Y3

T2 lesion-free

Patients were treated with alemtuzumab 12 mg at baseline and 12 months later

Re-treatment in Year 3 was administered upon recurrence of disease activity

18% of CARE-MS I patients and 20% of CARE-MS II patients were re-treated

with alemtuzumab in Year 3; <3% were treated with another DMT in Year 3

AAN 2014

Blitz S65-008

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

Brain volume loss should be included in our definition for NEDA

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

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.

Pros and cons of maintenance vs. induction therapies

Maintenance therapies

• Continuous treatment

• Low to very high efficacy

• Reversible

• Perceived to be lower risk

• Examples • Laquinimod, GA, IFN-beta, teriflunomide, BG12,

fingolimod, natalizumab, daclizumab

• Breakthrough disease • Suboptimal or failure to respond

• NEDA reliable metric for efficacy

• Rebound activity • Highly likely

• Can be life threatening

• Pregnancy • Contra-indicated

• No potential for a cure • Rebound

• SPMS & progressive brain atrophy

Induction therapies

• Short-courses or pulsed therapy

• Very high efficacy

• Irreversible

• Perceived to be higher risk

• Examples • Mitoxantrone, cladribine, alemtuzumab, anti-

CD20 (?), BMT

• Breakthrough disease • Marker for retreatment

• NEDA unreliable to assess efficacy

• Rebound activity • Less likely

• Unlikely to be life-threatening

• Pregnancy • Strategy of choice

• Potentially curative • 15-20 year experiment

• BMT, alemtuzumab, cladribine

T2T - NEDA

Zero Tolerance

Treatment objectives in relapsing MS

NEDA

Reduced ongoing

damage

Treat Early

T2T - NEDA

Zero Tolerance

Functional

Improvement

Maintain reserve

capacity


NEDA

Reduced ongoing

damage

Treat Early

T2T - NEDA

Zero Tolerance

Functional

Improvement

Maintain reserve

capacity


NEDA

Reduced ongoing

damage

CNS Repair

Healthy

ageing

Treat Early

T2T - NEDA

Zero Tolerance

Functional

Improvement

Maintain reserve

capacity


NEDA

Reduced ongoing

damage

CNS Repair

Healthy

ageing

Improved Quality of Life / Brain Health

Treat Early


Who is more risk averse?

1. MSers

2. Neurologists

3. Equally risk averse

Neurologists

Risk acceptance of PML (Survey 2009)

Putative risk rate to stop Tysabri treatment

Heesen et al. (2010) MSJ

WWW.MS-RES.ORG


Do you believe that we can cure MS?

1. Yes

2. No

3. Not sure

Possible

cure

The hypothetical Ideal

Reliable

long-term efficacy

Maintaining

QOL

Maintaining

independence

Maintaining the

ability to work

No issue for

pregnancy/fertility

Maximum reduction

of MS disease activity

Maximum

tolerability

Maximum

safety

Ease of

use

Minor impact on

everyday life

Survival Curves

85%

50%

30%

0%

15yrs 25yrs 40yrs 50yrs

100%

Natural history

Survival Curves

85%

50%

30%

0%


100% Benign MS

Natural history

Survival Curves

85%

50%

30%

0%


100% Benign MS

Natural history

Delayed onset of SPMS

Survival Curves

85%

50%

30%

0%


100% Benign MS

Natural history

Unrealistic expectation


Survival Curves

85%

50%

30%

0%


100% Benign MS

Proportioned of treated MSers are cured

Natural history

Unrealistic expectation


Defining a cure: a working definition

85%

50%

30%

0%


100%

Proportioned of treated MSers are cured

Natural history

A cure is NEDA (no evident disease activity) x 15 years


Do you believe that we can cure MS?

1. Yes

2. No

3. Maybe

Maybe The experiment is ongoing

Conclusions • MS is a bad disease

• Mortality, disability, unemployment, divorce, cognitive impairment, etc.

• Early highly-effective therapy is the only realistic option of preventing end-organ damage

• Now an established treatment option in the EU

• NEDA and T2T are current treatment target (zero tolerance)

• Beyond NEDA we need to target end-organ damage (brain atrophy and CSF NF levels)

• We need an acceptable working definition of an MS cure • NEDA x 15 years?

• Only possible with induction therapies (alemtuzumab, cladribine, BMT)

• Is it fair to make MSers wait 20 years for the outcome of an ongoing experiment?

• Can we cure MS?

• Risks and benefits • Who should take the risks?

• Who should make the decisions?

• What is the role of the healthcare professional in decision-making?

Benefit Risk from a Healthcare Provider Perspectiive

Health & Medicine

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