Multiple Sclerosis;

Introduction

George Katsamakis, MD

Northwest Neurology

Multiple Sclerosis Center

Multiple Sclerosis

• US prevalence: ~400,000

• Females:males: 2:1

• Median age of onset: 30 years

• ~85% begin as relapsing form

• Pathophysiology▪ Inflammation, white matter > gray matter

▪ Immune mediated

▪ Sequelae: demyelination, axonal transection, neurodegeneration

1. National MS Society Information Sourcebook.

2. Noonan CW et al. Neurology. 2002;58:136-138.

3. Weinshenker BG et al. Brain. 1989;112:133-146.

4. Compston A. McAlpine’s Multiple Sclerosis. 4th ed. London: Churchill Livingstone; 2005.

Potential Triggers for Multiple Sclerosis

Environmentalfactors

Abnormal immunologic response

Genetic predisposition

Infectious agent

MS

MS = multiple sclerosis

Gilden DH Lancet Neurol 2005;4:195-202, Noseworthy et al. N Engl J Med 2000;343:938

How does MS attack?

Nerves act like wires in the body

Most healthy nerve fibers (axons) have a shield (myelin) to protect them

With MS, the myelin is attacked by the immune system, causing lesions

This damage interferes with the messages that are sent by the nerves to the body, causing the major symptoms of MS

Inflammatory Mechanisms in MS

BBB = blood-brain barrier

Martino et al. J Neuroimmunol 2000;109:3, Trapp et al. N Engl J Med 1998;338:278, Lucchinetti et al.

Ann Neurol 2000;47:707-17, Fisher et al. Neurology 2002;59:1412-20

CNS inflammation

▪ Activation and CNS entry of peripheral immune cells

– T cells specific for myelin antigens

– Auto-antibody producing B cells

▪ BBB breakdown

▪ Demyelination

▪ Axonal injury

▪ Brain atrophy

Conventional MRI in MS Clinical Practice

T2

T1 Gd+Acitive BBB breakdown

T1 precontrast

Black Holes

The strongest correlation

with progression of disability

FLAIRVolume of disease

Disease Types

•Clinically isolated syndrome (CIS)

•Relapsing-remitting MS (RRMS)

▪ About 85% of people are diagnosed with RRMS

•Primary progressive MS (PPMS)

▪ About 15% of people experience this course

•Relapsing Progressive

•Secondary progressive

▪ Most people diagnosed with RRMS will eventually

transition to SPMS

Lublin et al, 2014

Can we predict whether the course of MS will be mild or severe?

Predicting a Patient's Natural History of Disease Using the MSSS May Help Guide Treatment Decisions1,2

1. Pachner AR et al. J Neurol Sci. 2009;278:66-70. 2. Figure adapted from Roxburgh RHSR et al. Neurology. 2005;64:1144-1151.

0 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 7 7.5 8 8.5 9 9.5 EDSS

1 0.67 2.44 4.30 5.87 7.08 7.93 8.64 9.09 9.35 9.50 9.63 9.74 9.84 9.90 9.94 9.97 9.98 9.98 9.99

2 0.53 2.01 3.69 5.24 6.46 7.27 7.98 8.58 8.95 9.18 9.38 9.59 9.79 9.88 9.93 9.97 9.99 9.99 9.99

3 0.45 1.77 3.34 4.82 6.00 6.81 7.54 8.14 8.55 8.83 9.07 9.35 9.63 9.77 9.86 9.92 9.97 9.98 9.99

4 0.35 1.45 2.87 4.27 5.41 6.24 6.98 7.65 8.12 8.42 8.70 9.08 9.47 9.68 9.80 9.88 9.95 9.98 9.99

5 0.30 1.28 2.60 3.90 4.95 5.79 6.58 7.26 7.75 8.08 8.38 8.83 9.32 9.60 9.76 9.86 9.95 9.98 9.99

6 0.25 1.13 2.33 3.54 4.55 5.38 6.14 6.81 7.33 7.66 7.98 8.50 9.08 9.45 9.68 9.81 9.93 9.97 9.99

7 0.24 1.04 2.10 3.17 4.13 4.96 5.75 6.46 6.98 7.32 7.65 8.24 8.91 9.33 9.59 9.76 9.90 9.95 9.99

8 0.21 0.94 1.92 2.93 3.81 4.57 5.36 6.10 6.61 6.95 7.32 7.97 8.71 9.21 9.55 9.74 9.89 9.96 9.99

9 0.21 0.88 1.76 2.65 3.45 4.17 4.93 5.64 6.14 6.50 6.90 7.65 8.53 9.09 9.47 9.70 9.87 9.95 9.99

10 0.19 0.78 1.53 2.34 3.10 3.79 4.55 5.28 5.77 6.14 6.58 7.39 8.31 8.92 9.34 9.61 9.83 9.94 9.99

11 0.17 0.71 1.40 2.13 2.82 3.46 4.21 4.94 5.42 5.82 6.30 7.18 8.15 8.79 9.24 9.52 9.78 9.92 9.98

12 0.16 0.64 1.28 1.98 2.64 3.25 3.94 4.63 5.13 5.54 6.03 6.92 7.93 8.63 9.13 9.43 9.71 9.88 9.97

13 0.13 0.58 1.14 1.80 2.44 3.05 3.70 4.38 4.91 5.32 5.80 6.74 7.83 8.55 9.03 9.34 9.65 9.85 9.96

14 0.11 0.49 1.03 1.70 2.33 2.91 3.55 4.26 4.82 5.23 5.70 6.56 7.59 8.34 8.86 9.20 9.57 9.82 9.95

15 0.10 0.45 0.99 1.64 2.26 2.82 3.44 4.14 4.68 5.09 5.51 6.33 7.41 8.17 8.70 9.11 9.51 9.78 9.94

16 0.09 0.38 0.85 1.42 1.99 2.56 3.17 3.86 4.41 4.81 5.18 6.00 7.14 7.97 8.54 9.04 9.49 9.75 9.94

17 0.05 0.32 0.76 1.28 1.77 2.30 2.95 3.65 4.17 4.55 4.94 5.74 6.89 7.77 8.38 8.99 9.52 9.79 9.96

18 0.04 0.26 0.66 1.12 1.57 2.09 2.70 3.37 3.89 4.27 4.62 5.43 6.62 7.54 8.23 8.94 9.51 9.78 9.96

19 0.05 0.28 0.63 1.00 1.39 1.89 2.50 3.19 3.72 4.12 4.49 5.35 6.59 7.51 8.22 8.98 9.57 9.81 9.96

20 0.05 0.26 0.59 0.94 1.29 1.71 2.29 2.99 3.51 3.93 4.30 5.15 6.43 7.45 8.23 8.98 9.58 9.80 9.95

21 0.05 0.30 0.66 1.02 1.39 1.77 2.34 2.97 3.43 3.83 4.21 5.09 6.35 7.33 8.08 8.87 9.49 9.77 9.96

22 0.04 0.23 0.54 0.90 1.28 1.66 2.20 2.82 3.29 3.69 4.09 5.04 6.35 7.35 8.10 8.84 9.42 9.73 9.95

23 0.05 0.27 0.58 0.91 1.26 1.64 2.19 2.78 3.21 3.69 4.19 5.16 6.47 7.46 8.20 8.87 9.43 9.75 9.95

24 0.05 0.24 0.52 0.86 1.25 1.63 2.15 2.71 3.09 3.52 4.01 5.03 6.36 7.38 8.15 8.81 9.39 9.74 9.96

25 0.05 0.23 0.47 0.77 1.15 1.56 2.05 2.53 2.84 3.21 3.74 4.88 6.26 7.24 8.00 8.73 9.35 9.75 9.98

26 0.05 0.20 0.45 0.78 1.17 1.58 2.08 2.63 2.99 3.40 3.95 5.02 6.39 7.44 8.21 8.89 9.48 9.80 9.96

27 0.05 0.22 0.48 0.78 1.15 1.56 2.03 2.56 2.91 3.29 3.86 4.93 6.33 7.38 8.14 8.91 9.56 9.85 9.98

28 0.04 0.17 0.40 0.74 1.16 1.52 1.88 2.39 2.76 3.04 3.46 4.54 5.99 7.07 7.90 8.75 9.45 9.80 9.98

29 0.03 0.18 0.47 0.80 1.19 1.51 1.79 2.27 2.68 3.01 3.41 4.35 5.66 6.76 7.66 8.62 9.38 9.75 9.96

30 0.01 0.13 0.45 0.82 1.19 1.45 1.69 2.23 2.75 3.13 3.50 4.35 5.61 6.66 7.54 8.47 9.27 9.67 9.91

Years

=1st Decile

=2nd Decile

=3rd Decile

=4th Decile

=5th Decile

=6th Decile

=7th Decile

=8th Decile

=9th Decile

=10th Decile

10

Patient and Disease Heterogeneity

Mild-mod

disabilityCane

Negative Prognostic Indicators

•Male Gender

•Frequent, multifocal attacks

•Poor response to steroids

•Heavy MRI burden on initial scans

•Pyramidal/motor involvement

•Ataxia

•Cognitive difficulties

•5 year accumulation of disability

•Spinal progression (primary progressive MS)

Natural History of Untreated MS

• 50% of patients with RR-MS develop progressive MS within

10-15 years

• 90% of patients with RR-MS will eventually (over 25 years)

develop SP-MS

• 43%-65% of patients will develop cognitive impairments

RR-MS = relapsing-remitting MS; SP-MS = secondary progressive MS.Weinshenker et al. Brain. 1989;112:133; Rao et al. Neurology. 1991;41:692.

MS Develops in the Majorityof Patients With Abnormal MRI

at Initial Presentation (CIS)

0

90

30

60

% o

f p

ati

en

ts w

ith

CD

-MS

5 years

10 years

69

83

511

CIS with initially

abnormal MRI

CIS with initially

normal MRI

Adapted from Sailer et al. Neurology. 1999;52:599.

Severity of MS After 10 Years According to Lesion Load at Presentation

Adapted from Sailer et al. Neurology. 1999;52:599.

0

100

20

60

40

80

% o

f p

ati

en

ts

EDSS >3

EDSS >6 (cane)

No MRI

abnormalities

19

4

T2 lesion

volume <3 cm3

27

18

T2 lesion

volume >3 cm3

90

45

1000

AP

P*-

Po

sit

ive

Ce

lls

/mm

2

Disease Duration (years)

00–1

500

1000

3500

1–5 5–10 >10

Axonal Damage in MS: May Occur Early During the Disease Process

RMS=relapsing multiple sclerosis. Figure adapted from Kuhlmann T et al. Brain. 2002;125:2202-2212.

* Amyloid precursor protein

(APP) = marker of axonal damage

More damage Less damage

In a retrospective analysis of brain tissue from 39 patients,

axonal damage in lesions of individuals with RMS was most

prominent during the first year of the disease

Axonal damage

Earlier Later

15

Initiating Timely Treatment May Delay Progression to SPMS

In one study of 532 patients with MS, treatment reduced the risk of progressing

to SPMS in both high-risk and low-risk patients*

High-Risk Patients* Low-Risk Patients*

1.0

0.8

0.6

0.4

0.2

0.0

0 5 10 15 20 25 30 35 40 45 50

Time (years)

Pro

gre

ss

ion

-Fre

e

Su

rviv

al

Pro

ba

bilit

y

1.0

0.8

0.6

0.4

0.2

0.0

0 5 10 15 20 25 30 35 40 45 50

Time (years)

Pro

gre

ss

ion

-Fre

e

Su

rviv

al

Pro

ba

bilit

y

148 148 143 107 47 16 8115 101 81 49 24 14 4

Treated with

DMTsUntreated

158 158 157 96 55 15 12111 109 103 67 46 20 8

Treated with

DMTsUntreated

P<0.000001 P<0.0004

Treated

Untreated

Treated

Untreated

* Risk is defined as the likelihood of progressing to SPMS using a pre-defined risk score (Bayesian risk estimate for MS, BREMS); High risk ≥75th percentile; Low risk ≤25th percentile Bergamaschi R et al. Mult Scler. 2012;0:1-9.

16

Treatment May Reduce the Risk of Long-Term Disability Progression

Reduction in risk of progression

to EDSS 3.0 in 1735 treated patients compared with 781 untreated patients

with a median follow-up of 12 years

Reduction in risk of progression

to EDSS 6.0 in 1904 treated patients compared with 539 untreated patients

with a median follow-up of 12 years

90%

62%

Cocco E et al. Mult Scler. 2015;21:433-441. 17

In one observational study involving 3060 MS patients, the risk of long-term disability

progression was reduced for patients treated with immunomodulatory or

immunosuppressive therapies compared to untreated patients

DS

S*

Sc

ore

Years From Clinical Onset of MS

6

5

4

3

2

1

00 5 10 15 20 25 30

7

Phase 2

Phase 1

Natural History

Disability in MS Is Thought to Progress in Two Phases1,2

* The Disability Status Scale (DSS) is a modified EDSS where each half-step was included with the corresponding whole unit, leading to a 10-step scale very similar to (if not exactly the same as) the EDSS.

1. Figure adapted from Leray E et al. Brain. 2010;133:1900-1913. 2. Steinman L. Multiple sclerosis: a two-stage disease. Nat Immunol. 2001;2:762-764.

In a retrospective study of 718 patients, it was observed that once DSS* 3 was

reached, disability progressed at a relatively steady rate,

regardless of the progression rate from 0 to 3

18

Patient and Disease Heterogeneity

Multiple Sclerosis;

Treatment Options

Immunologic

Implications

George Katsamakis, MD

Northwest Neurology

Multiple Sclerosis Center

Natalizumab Tysabri

MS Therapy Options

Currently, FDA-approved therapies for MS

1868-1993 Nothing

1993 Interferon beta-1b (Betaseron)

1996 Interferon beta-1a, IM (Avonex)

1997 Glatiramer acetate (Copaxone)

≈2000 Mitoxantrone (Novantrone)

≈2003 Interferon beta-1a, SC (Rebif)

2006 Natalizumab (Tysabri)

2010 Fingolimod (Gilenya)

2012 Teriflunomide (Aubagio)

2013 Dimethylfumarate (Tecfidera)

2015 Alemtuzmab (Lemtrada)

?2016/2017 Ocrelizumab (Ocrevus)

22

23

Tysabri:Progressive Multifocal Leukoencephalopathy

• Viral brain infection (JC virus)

• Over 500 cases

• Incidence varies with presence of risk factors

• Progresses to severe disability or death

• Plasma exchange helps clear natalizumab

- Is followed by immune reconstitution inflammatory syndrome in

almost all cases (IRIS)

1. Tysabri [PI]. Cambridge, Mass: Biogen Idec; 2011. 2. Sandrock A, et al. 63rd

AAN; April 9-16, 2011; Honolulu, Hawaii. Poster P03.248.

Tysabri 7 year long term efficacy

Kappos L,1 Butzkueven H,2,3 Spelman T,2 Trojano M,4 Wiendl H,5 Chen Y,6 Ho PR,6 Koendgen H,6 Campbell N6

Relapse rates

Progression of disability

Alemtuzumab Lemtrada

Alemtuzumab (Lemtrada)

• Humanized monoclonal antibody directed against CD52 antigen

• CD52 is a cell-surface glycoprotein of unknown function, present on most T-cells, B-cells, NK cells, dendritic cells, eosinophils, monocytes, macrophages

• Depletes CD52-expressing cells

• Annual infusion given with corticosteroids

Alemtuzumab’s Proposed Mechanism of Action in MS Alemtuzumab is a monoclonal antibody that

binds to the CD52 surface antigen expressed highly on T and B lymphocytes, and expressed at lower levels on natural killer cells, monocytes, and macrophages1,2

Following alemtuzumab administration, a

distinctive pattern of T- and B-cell repopulation

begins within weeks, potentially changing the

balance of the immune system3,4

– B-cell counts usually recovered within six months1

– T-cell counts increased more slowly and usually

remained below baseline 12 months after

treatment1

– Approximately 60% of patients had lymphocyte

counts below normal levels 6 months after each

course; 20% had counts below normal level after 12

months1

Alemtuzumab alters the proportions of some

lymphocyte subsets, including an increased

proportion of T regulatory (Treg) cells5,6

a Alemtuzumab was administered at Months 0 and 12.

CARE-MS=Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis; LLN=lower limit of normal

1. LEMTRADA (alemtuzumab) Prescribing Information. Sanofi Genzyme, USA; Nov 2014; 2. Turner MJ et al. J Neuroimmunol 2013;261:29-

36; 3. Hu Y et al. Immunology 2009;128:260-70; 4. Fox EJ. Expert Rev Neurother 2010;10:1789-97; 5. Cox AL et al. Eur J Immunol

2005;35:3332-42; 6. Hartung HP et al. ECTRIMS 2012, Poster P935; 7. Coles AJ et al. Lancet 2012;380:1829-39.

Treg Cells as Percentage of Total CD4+ Count6,a

2

6

10

14

0 1 3 6 9 12

CD

4+

Tre

gC

ell C

ou

nts

(%

)

4

8

12

SC IFNB-1a 44 μg

Alemtuzumab 12 mg

13 15 18 21 24

16

Months

Alemtuzumab course

White Blood Cell Counts Following Alemtuzumab:

CARE-MS I and CARE-MS II7

LLN

Follow-up Month

Cell C

ou

nts

(10

9/L

)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

0 2 4 6 8 10 12 14 16 18 20 22 24

LymphocytesNeutrophils

MonocytesEosinophilsBasophils

Alemtuzumab course

Alemtuzumab’s exact mechanism of action

is unknown

Lemtrada pros & cons

• Infrequent dosing

• Efficacy over interferon impressive

• 49% reduction in relapse rate

• 42% reduction in progression of disability

• Long term efficacy seems durable;

• 8 year follow up suggest up 67% do not need additional doses

• Side effects include infusion reactions, thyroid disorders, bleeding

disorder, kidney inflammation

• Long term risk unknown

• ? Rescue if it doesn't work

Alemtuzumab Safety Profile

• Cytokine release syndrome: fever, rash, headache, nausea/vomiting, rigor

• Autoimmune disease (primarily thyroid dysfunction): 30%

• Immune thrombocytopenic purpura: ~3%

• Glomerular nephritis: <1%

• Infections (~66%): upper and lower respiratory tract, urinary tract, herpes, influenza

• Cancers: Burkitt’s lymphoma, breast cancer, cervical cancer

• Serious infusion reactions: 1.4%

Alemtuzumab Safety Profile Through 5 Years

Identified Risks Overview

Infusion reactions (IRs)2 • The most common adverse events were mild-to-moderate IRs

Infections3-5

• Infections were common with LEMTRADA treatment; most were mild-mod

• 40-60%, highest in the first year

• Serious infections <2%

Autoimmune AEs3 • A monitoring program was implemented for early detection of autoimmune AEs

Thyroid disorders6

• Protocol-specified safety monitoring and education helped with early detection

and effective treatment of thyroid AE’s

• Can be as high as 30%

Immune thrombocytopenia

(ITP)7

• 2.3% overall during the study and extension

• Most patients responded to first-line therapy

Nephropathy8

• Glomerulonephritis cases in the MS clinical program were detected by the

safety monitoring program

• 0.3% overall during the study and extension

A total of 1486 patients have been treated with LEMTRADA in the phase 2

and 3 trials and the extension study, representing 8266 total patient-years

of follow-up

▪ Median follow-up time was 5.9 years (range, 1–12)

Alemtuzumab Overview of Safety Phase 2 and 3 Core and Extension Studies

Efficacy outcomes from the CARE-MS core and extension

▪ 68% and 60% of treatment-naïve and previously treated patients received no additional alemtuzumab treatment

courses through Year 51,2

▪ EDSS scores remained stable or improved in 82.2% and 77% of treatment-naïve and previously treated patients

through Year 51,2

▪ 33% and 43% of treatment-naïve and previously treated patients achieved confirmed disability improvement through

Year 53,4

Safety outcomes from the CARE-MS core and extension

▪ The most common adverse events were IRs2,5

– Patients received pretreatment and symptomatic treatment as needed5,6

▪ Over years 0-4, Infections with alemtuzumab treatment were mostly mild-to-moderate (Grade 1 to Grade 2: 54.5% to

71.1%) and responded to conventional therapy7

▪ Alemtuzumab treatment is associated with autoimmune AEs, including thyroid disorders (ranged from 5.7 % to 20.9%

[over 0-5 years]): ITP (2.0%), and nephropathies (0.3%, CARE-MS I and 0.2%, CARE-MS II [cumulative, 0-5

years])1,2,8,9

– Proactive safety procedures, including physician and patient education and regular laboratory monitoring, helped

with early detection and treatment of autoimmune disorders10

▪ Alemtuzumab may be associated with an increased risk of malignancy including thyroid, melanoma, and

lymphoproliferative disorders11

Summary: Alemtuzumab Benefit:Risk in RRMS Patients

1. Limmroth V et al. AAN 2016, S51-004; 2. Coles A et al. AAN 2016, P3.022; 3. Havrdova E et al. ECTRIMS 2015, Platform; 4. Fox E et al.

ECTRIMS 2015, P1102; 5. Caon C et al. Int J MS Care 2015 2015;17:191-8; 6. Caon C et al. CMSC 2012, DX41; 7. Jung-Henson L et al. AAN

2015, P7.265; 8. Senior PA et al. AAN 2016, P2.086; 9. Cuker A. et al. ECTRIMS 2015, P590; 10. Fox E et al. AAN 2013, S41.001; 11. LEMTRADA

(alemtuzumab) Prescribing Information, Genzyme Corporation, USA; Nov 2014.

CARE-MS I Core and Extension: No Evidence of Disease Activity Through Year 5a

aNo evidence of disease activity is defined as no evidence of clinical disease activity (relapse and 6-month CDW) and MRI activity (new

gadolinium [Gd]-enhancing lesions, and new/enlarging T2 hyperintense lesions). bPatients treated with alemtuzumab 12 mg in the core

studies. 1. Compston DA et al. AAN 2015, S4.007; 2. Havrdova E. ECTRIMS 2015, Platform 152; 3. Data on File. Genzyme Corporation.

• The majority of alemtuzumab-treated patients had NEDA in Years 3, 4 and 5

37.9

46.850.1

67.561.7 60.2 62.4

0

20

40

60

80

100

Year 1 Year 2 Year 3 Year 4 Year 5

Pro

po

rtio

n o

f P

ati

en

ts W

ith

N

ED

A,

% (

95

% C

I)QoL and 6-Month Sustained Reduction in Disability

p=0.0053

(↑32.2%)

p<0.0001

(↑44.5%)74% of patients did not receive

alemtuzumab treatment since

Month 12b

Proportion of Patients With NEDA Over 5 Years1-3

174 369 169 354 326 324No. of patients 319

Pre-specified Endpoint

Extension Study

Tertiary Endpoint

Core Study

SC IFNB-1a 44 μg Alemtuzumab 12 mg

Orelizumab Ocrevus(pending FDA approval)

Ocrelizumab

• Monoclonal Ab to CD20.

• Targets intermediate B cells

• 2 studies were done against interferon (Rebif):

• ARR was reduced by ~46% (over inteferon)

• Disability was reduced by ~40% (over interferon)

• New T2 MRI lesions reduced by ~80% (over interferon)

• Active MRI lessons reduced by ~95% (over interferon)

Ocrelizumab

• Infrequent dosing

• Infusion related reactions are mild and managable

• Adverse events and side effects were minimal

• Does it work in PPMS? EDSS was reduced by 24%

• Novel mechanism of action; targets B cells

• Long term safety?

• Signal for cancer risk

Predicting a Patient's Natural History of Disease Using the MSSS May Help Guide Treatment Decisions1,2

1. Pachner AR et al. J Neurol Sci. 2009;278:66-70. 2. Figure adapted from Roxburgh RHSR et al. Neurology. 2005;64:1144-1151.

0 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 7 7.5 8 8.5 9 9.5 EDSS

1 0.67 2.44 4.30 5.87 7.08 7.93 8.64 9.09 9.35 9.50 9.63 9.74 9.84 9.90 9.94 9.97 9.98 9.98 9.99

2 0.53 2.01 3.69 5.24 6.46 7.27 7.98 8.58 8.95 9.18 9.38 9.59 9.79 9.88 9.93 9.97 9.99 9.99 9.99

3 0.45 1.77 3.34 4.82 6.00 6.81 7.54 8.14 8.55 8.83 9.07 9.35 9.63 9.77 9.86 9.92 9.97 9.98 9.99

4 0.35 1.45 2.87 4.27 5.41 6.24 6.98 7.65 8.12 8.42 8.70 9.08 9.47 9.68 9.80 9.88 9.95 9.98 9.99

5 0.30 1.28 2.60 3.90 4.95 5.79 6.58 7.26 7.75 8.08 8.38 8.83 9.32 9.60 9.76 9.86 9.95 9.98 9.99

6 0.25 1.13 2.33 3.54 4.55 5.38 6.14 6.81 7.33 7.66 7.98 8.50 9.08 9.45 9.68 9.81 9.93 9.97 9.99

7 0.24 1.04 2.10 3.17 4.13 4.96 5.75 6.46 6.98 7.32 7.65 8.24 8.91 9.33 9.59 9.76 9.90 9.95 9.99

8 0.21 0.94 1.92 2.93 3.81 4.57 5.36 6.10 6.61 6.95 7.32 7.97 8.71 9.21 9.55 9.74 9.89 9.96 9.99

9 0.21 0.88 1.76 2.65 3.45 4.17 4.93 5.64 6.14 6.50 6.90 7.65 8.53 9.09 9.47 9.70 9.87 9.95 9.99

10 0.19 0.78 1.53 2.34 3.10 3.79 4.55 5.28 5.77 6.14 6.58 7.39 8.31 8.92 9.34 9.61 9.83 9.94 9.99

11 0.17 0.71 1.40 2.13 2.82 3.46 4.21 4.94 5.42 5.82 6.30 7.18 8.15 8.79 9.24 9.52 9.78 9.92 9.98

12 0.16 0.64 1.28 1.98 2.64 3.25 3.94 4.63 5.13 5.54 6.03 6.92 7.93 8.63 9.13 9.43 9.71 9.88 9.97

13 0.13 0.58 1.14 1.80 2.44 3.05 3.70 4.38 4.91 5.32 5.80 6.74 7.83 8.55 9.03 9.34 9.65 9.85 9.96

14 0.11 0.49 1.03 1.70 2.33 2.91 3.55 4.26 4.82 5.23 5.70 6.56 7.59 8.34 8.86 9.20 9.57 9.82 9.95

15 0.10 0.45 0.99 1.64 2.26 2.82 3.44 4.14 4.68 5.09 5.51 6.33 7.41 8.17 8.70 9.11 9.51 9.78 9.94

16 0.09 0.38 0.85 1.42 1.99 2.56 3.17 3.86 4.41 4.81 5.18 6.00 7.14 7.97 8.54 9.04 9.49 9.75 9.94

17 0.05 0.32 0.76 1.28 1.77 2.30 2.95 3.65 4.17 4.55 4.94 5.74 6.89 7.77 8.38 8.99 9.52 9.79 9.96

18 0.04 0.26 0.66 1.12 1.57 2.09 2.70 3.37 3.89 4.27 4.62 5.43 6.62 7.54 8.23 8.94 9.51 9.78 9.96

19 0.05 0.28 0.63 1.00 1.39 1.89 2.50 3.19 3.72 4.12 4.49 5.35 6.59 7.51 8.22 8.98 9.57 9.81 9.96

20 0.05 0.26 0.59 0.94 1.29 1.71 2.29 2.99 3.51 3.93 4.30 5.15 6.43 7.45 8.23 8.98 9.58 9.80 9.95

21 0.05 0.30 0.66 1.02 1.39 1.77 2.34 2.97 3.43 3.83 4.21 5.09 6.35 7.33 8.08 8.87 9.49 9.77 9.96

22 0.04 0.23 0.54 0.90 1.28 1.66 2.20 2.82 3.29 3.69 4.09 5.04 6.35 7.35 8.10 8.84 9.42 9.73 9.95

23 0.05 0.27 0.58 0.91 1.26 1.64 2.19 2.78 3.21 3.69 4.19 5.16 6.47 7.46 8.20 8.87 9.43 9.75 9.95

24 0.05 0.24 0.52 0.86 1.25 1.63 2.15 2.71 3.09 3.52 4.01 5.03 6.36 7.38 8.15 8.81 9.39 9.74 9.96

25 0.05 0.23 0.47 0.77 1.15 1.56 2.05 2.53 2.84 3.21 3.74 4.88 6.26 7.24 8.00 8.73 9.35 9.75 9.98

26 0.05 0.20 0.45 0.78 1.17 1.58 2.08 2.63 2.99 3.40 3.95 5.02 6.39 7.44 8.21 8.89 9.48 9.80 9.96

27 0.05 0.22 0.48 0.78 1.15 1.56 2.03 2.56 2.91 3.29 3.86 4.93 6.33 7.38 8.14 8.91 9.56 9.85 9.98

28 0.04 0.17 0.40 0.74 1.16 1.52 1.88 2.39 2.76 3.04 3.46 4.54 5.99 7.07 7.90 8.75 9.45 9.80 9.98

29 0.03 0.18 0.47 0.80 1.19 1.51 1.79 2.27 2.68 3.01 3.41 4.35 5.66 6.76 7.66 8.62 9.38 9.75 9.96

30 0.01 0.13 0.45 0.82 1.19 1.45 1.69 2.23 2.75 3.13 3.50 4.35 5.61 6.66 7.54 8.47 9.27 9.67 9.91

Years

=1st Decile

=2nd Decile

=3rd Decile

=4th Decile

=5th Decile

=6th Decile

=7th Decile

=8th Decile

=9th Decile

=10th Decile

42

Patient and Disease Heterogeneity

Mild-mod

disabilityCane

Treat here!

Keep them here!