Defining goals and patient expectations

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.

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







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.

http://www.google.co.uk/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&docid=Jf7qSE1vr_MsKM&tbnid=RUrNdJjq2bTIYM:&ved=0CAUQjRw&url=http://www.drmortons.co.uk/blog/overloaded-doctors-want-to-put-off-time-wasters/&ei=fE0zUq7sDOb80QWCvICwDw&psig=AFQjCNGCXclA6XxtGFxbsoF-Tq0ijncXlg&ust=1379180225621820

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.


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



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


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+


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.


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


Freedom from

disease activity/

disease activity

free

Reduced ongoing

damage

Potential for CNS

repair

Maintain reserve

capacity

Treat Early






T2T - NEDA

Zero

tolerance


Freedom from

disease activity/

disease activity

free

Reduced ongoing

damage

Potential for CNS

repair

Maintain reserve

capacity

Functional

improvement

Healthy

aging

Treat Early






T2T - NEDA

Zero

tolerance


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






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



• Your choice?




• Adherence?


Monitoring

• MS prognosis



Rebaseline

Rebaseline:

• IFNβ, natalizumab, fingolimod,

terflunomide, DMF=3-6 months

• Glatiramer acetate=9 months

• Alemtuzumab=24 months

DMF=dimethyl fumarate.


Choosing therapy

X Y Z

Define the

Individual’s MS

No



• Your choice?




• Adherence?


Monitoring

• MS prognosis



Rebaseline

Rebaseline:





“Treat early”



Choosing therapy

X Y Z

Define the

Individual’s MS

No



• Your choice?




• Adherence?


Monitoring

• MS prognosis



Rebaseline

Rebaseline:





“Treat early”

“Choose treatments

individually”



Choosing therapy

X Y Z

Define the

Individual’s MS

No



• Your choice?




• Adherence?


Monitoring

• MS prognosis



Rebaseline

Rebaseline:





“Treat early”


individually”

“Monitor vigilantly”



Choosing therapy

X Y Z

Define the

Individual’s MS

No



• Your choice?




• Adherence?


Monitoring

• MS prognosis



Rebaseline

Rebaseline:





“Treat early”


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.

Health & Medicine

Defining goals and patient expectations