defining goals giovannoni berlin 4 5 may 2013

GAVIN GIOVANNONI BARTS AND THE LONDON

Defining Goals and Patient

Expectations: The Importance of

Early Planning

1

Consequences of Increasing EDSS Scores:

Loss of Employment

2

The proportion of patients employed or on long-term sick leave is calculated as a percentage of patients aged 65 or younger.

Kobelt G et al. J Neurol Neurosurg Psychiatry. 2006;77:918-926.

Austria

Belgium

Germany

Italy

Netherlands

Spain

Sweden

Switzerland

United Kingdom

Work Capacity by Disability Level P

rop

ort

ion

of

Pa

tie

nts

≤6

5 Y

ea

rs O

ld

Wo

rkin

g (

%)

0

10

20

30

40

50

60

70

80

90

0.0/1.0 2.0 3.0

EDSS Score

MS patient’s QoL decreases tremendously

dependent on the EDSS score

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 0.546 0.825 0.047

Switzerland 0.59 0.89 0.1

UK 0.51 0.92 0.18

EQ-5D was used to calculate utilities: Utility is a measure of people's well-being or preferences for outcomes.

Mean utilities and EDSS in Germany 1= perfect health; 0 = worst health/dead

Source: based on G. Kobelt et al.: The European Journal of Health Economics, Volume 7; suppl. 2006

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 1 (Kobelt G. et al. 1999)

0,00 - Worst possible status

1,00 - Best possible health status

0,55 - mean utility of patients with multiple sclerosis (Kobelt G. et al. 2001)

0,48 - mean utility of severe haemophilia patients with inhibitors (Ekert H. et al. 2001)

0,82 - mean utility of aging patients with osteoporosis,

no fracture (Oleksik A et al. 2000)

0,58 - mean utility of patients with Parkinson’s Disease (Siderowf A. et al. 2002)

Utilities make diseases comparable

MS is a disabling disease

Cognitive Dysfunction • Prevalence: 43% to 82%1,74

• Affects employment, activities of daily living, and social functioning2

Life Shortening • 5- to 7-year decrease in life

expectancy3-5

• 2- to 7-fold increase in suicide risk6

• 50% MS patients die of disease-related causes6

1Rao SM, et al. Neurology. 1991;41:685-691 2Rao SM, et al. Neurology. 1991;41:692-696 3Sadovnick AD, et al. Neurology. 1992;42:991-994 4Ebers GC. J Neurol Neurosurg Psychiatry. 2001;71:16-19 5Kingwell E, et al. J Neurol Neurosurg Psychiatry. 2012;83:61-6. 6Sadovnick AD, et al. Neurology. 1991;41:1193-1196. 7Giogkaraki et al., J Neurol Sci. 2008

survival analysis

“hit hard and early ”

MS is an autoimmune disease hypothesis

15-20 year experiment

What is your treatment philosophy?

maintenance-escalation vs. induction

7

MS Treatment Decisions Are Complex:

Some factors to consider…….

Patient Preferences

Therapy Attributes

Efficacy Safety Tolerability Administration (route/frequency) Monitoring requirements Biomarkers (e.g. NAb) Adherence

Socio-demographic profile (lifestyle, work, family) Risk tolerance Likelihood of adherence

Geographic/Economic Factors

8

Patient and Disease Profile

Age, gender Disease activity (MRI/clinical) Impairment/disability Treatment history Comorbidities Biomarkers (e.g., Anti-JCV Ab)

Label Reimbursement / access to drug

Shared Treatment Decision

Shared treatment decision that optimally weighs these

considerations to arrive at the therapy that best meets the

patient’s needs

Right Therapy, Right Patient, Right Time

Key Treatment Decision Steps

9

Monitoring:

Choosing therapy

X Y Z

Define the Individual’s Multiple Sclerosis

no

Treatment failure? yes

• Patient • MS prognosis • Life style and goals • Your goals for therapy

• Patient’s preferences? • Your choice?

Individual measures: • Evidence of disease activity? • Tolerability/safety? • Adherence? • Drug or inhibitory markers?

Monitoring

Right Therapy, Right Patient, Right Time

Key Treatment Decision Steps

10

Monitoring:

Choosing therapy

X Y Z

Define the Individual’s Multiple Sclerosis

no

Treatment failure? yes

• Patient • MS prognosis • Life style and goals • Your goals for therapy

• Patient’s preferences? • Your choice?

Individual measures: • Evidence of disease activity? • Tolerability/safety? • Adherence? • Drug or inhibitory markers?

Monitoring

vs.

1

2

3

Clinical

MRI

NABs

100 MSers Who are the responders?

~20% responders

~40% sub-optimal responders

~40% non-responders

Emerging concepts in MS

NEDA; no evidence of disease activity

TTT; treat-to-target

Treat-2-target

No Evidence of Disease Activity

Discussing Risk of therapies with Patients: How Willing

Are Patients to Accept Risk ?

Adapted from Heesen et al. Mult. Scler. 2010, 16:1507-1512

Success 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 of PML risk

stratification.

• Anti-JCV antibody testing is widely utilized 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.

Negative* Anti-JCV

Antibody Status ≤0.07/1000 95% CI: 0–0.48

FACTOR 1

Treatment exposure time or prior IS use do 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).

Biogen Idec, data on file.

Factors Predicting the Ultimate Goal of Disease

Activity Silencing

Havrdova E. et al., ECTRIMS Meeting poster 905, Gothenburg, Sweden 2010 Havrdova E. et al. Neurology 2010 ;74:S3-7.

Variables Associated with Overall Freedom from Disease Activity (No Clinical or MRI Activity) over 2 Years in a Multivariate Logistic Regression Analysis

AFFIRM

Natalizumab-treated patients with fewer relapses, fewer MRI lesions, and lower EDSS scores at therapy initiation and who did not develop persistent anti-natalizumab antibodies were more likely to achieve freedom from disease activity over the course of the 2-year AFFIRM study.

Can Stabilize the Disease, Not Revert it

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.

22

Baseline EDSS Score ≤3.0 (n=1591)

Baseline EDSS Score >3.0 (n=1840)

Natalizumab should be used according to the SmPC

TOP: Overall Stabilization of EDSS Scores in Patients with Either a High or Low Starting EDSS

Conclusions

• NEDA, T2T and DAF have entered the neurology lexicon

• We need an acceptable working definition of an MS cure

• DAF x 15 years?

• Should the definition be disease-stage specific?

• How do we deal with maintenance and induction therapies?

• Maintenance - absence of NEDA status indicates non-response

• Induction – absence of NEDA status indicates a time to retreat

• Improve risk mitigation tool

• Who should make the decision re early aggressive treatment?

• Regulators

• Payers

• Neurologists

• MSers

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

• For example, alemtuzumab extension study

• What do we do about post-inflammatory neurodegeneration?

• We need better outcomes, e.g. regional brain atrophy and CSF neurofilament levels

• Neuroprotective treatments