personalised medicine ecf

Personalised Medicine

Gavin Giovannoni

Version 2.0

Disclosures

Over the last 15 years I have received personal compensation for participating in advisory boards in relation to clinical trial design, trial steering committees, and data and safety monitoring committees from: Abbvie, Bayer-Schering Healthcare, Biogen, Canbex, Eisai, Elan, Fiveprime, Genzyme, Genentech, GSK, GW Pharma, Ironwood, MSD, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals

Patient

Healthcare Professional(HCP)

ESF December 2012

http://www.esf.org/coordinating-research/forward-looks/biomedical-sciences-med/current-forward-looks-in-biomedical-sciences/personalised-medicine-for-the-european-citizen.html



Patient

HCP

Patie

nt HCP

Health Service

Pers

onal

ised

Med

icin

e Precision Medicine

Value

Classification of MS

Multiple Sclerosis

Shared decision-making

Health Services

Databasing

Research Personalised Medicine1. Disease

a. Multiple sclerosisb. Classification

2. Research3. Databasing4. Shared-decision making5. Health Services

Objectives

MRI Lesions

1st clinicalattack

Time (Years)

Asymptomaticdisease

Inflammation

Brain volume lossNerve cell loss

Dise

ase

Seve

rity

SPMSRRMS

1st MRI lesion

Relapses

CISRIS R-SPMS

RIS = radiologically isolated syndrome (asymptomatic MS)CIS = clinically isolated syndromeRRMS = relapsing-remitting MS R-SPMS = relapsing secondary progressive MSSPMS = secondary progressive MSPPMS = primary progressive MS

PPMS

EDSS < 4.0 / ? Age < 40

Disease & Taxonomy

1. When does MS begin?2. When does the progressive phase begin?3. Is MS really 2 or 3 diseases?4. Is there such a thing as therapeutic window?

When does MS begin?

Impact of MS: cognitive functioning in the CIS stage

Feuillet et al. MSJ 2007

CIS Patients n = 40

Healthy Controlsn = 30

p < 0.0001

Deficits were found mainly in memory, speed of information

processing, attention and executive functioning.

Patients failing ≥ 2 cognitive

tests

Association of MRI metrics and cognitive impairment in radiologically isolated syndromes

Amato et al. Neurology. 2012 Jan 31;78(5):309-14.

AAN 2013

The data presented for years 5, 10, 14, and 20 were obtained from different publications based on the same longitudinal study. The exact relationship between MRI findings and the clinical status of the patient is unknown.

Fisniku LK et al. Brain. 2008;131:808-817; Morrissey SP et al. Brain. 1993;116:135-146; O’Riordan JI et al. Brain. 1998;121:495-503; Brex PA et al. N Engl J Med. 2002;346:158-164.

Baseline number of brain lesions predicts progression to EDSS Score ≥3.0

Queen Square Study

When does the progressive phase begin?

Rapid Decline in Health Status With Increasing Disability Occurs Early in MS (Before EDSS 2.5)

a Utility score <0 indicates MSers felt their health status was worse than death. EDSS=Expanded disability Status Scale1. Orme M et al. Value Health 2007;10:54-60; 2. Zwibel HL, Smrtka J. Am J Manag Care 2011;17( Suppl 5):S139-45. Figure adapted from Naci H et al. J Med Econ 2010;13:78-89.

Relationship Between EDSS and Health Status1,2

1.0

0.8

0.6

0.4

0.2

0

–0.2

–0.4

0 1 2 3 4 5 6 6.5 7 8 9

Heal

th S

tatu

s (U

tility

)

EDSS

Essentially restricted to bed, chair, or wheelchair

AustriaBelgiumGermany Italy The NetherlandsSpainSwedenSwitzerlandUK UKa

Perfect health

Death

SPMS

Brain atrophy occurs across all stages of the disease

De Stefano, et al. Neurology 2010

n= 963 MSers

Is MS really 2 or 3 diseases?

Is multiple sclerosis?

a. One disease

b. Two diseases; relapse-onset and primary progressive MS

c. Three diseases; relapsing-remitting MS, secondary progressive MS and primary progressive MS

MRI Lesions

1st clinicalattack

Time (Years)

Asymptomaticdisease

Inflammation


Dise

ase

Seve

rity

SPMSRRMS

1st MRI lesion

Relapses

CISRIS R-SPMS


PPMS

EDSS < 4.0 / ? Age < 40

Disease & Taxonomy

Is MS really 2 or 3 diseases?

1983 U.S. Orphan Drug Act

● Eligibility– Disease affects few people in U.S. (<200,000)– Or no reasonable expectation that profitable– Low expected returns sufficient not necessary

● Incentives– R&D tax credits: ½ clinical, even if not approved– Clinical research grant programs– FDA counseling and priority review– Guaranteed market exclusivity of 7 years

#MS-is-1-not-2-or-3-diseases

Progressive MS: 2014 Definitions

Progressive Disease

Progressive accumulation of disability from onset(PP)

Progressive accumulation of disability after initial relapsing

course

(SP)

Active and with progression

Active but without progression

Not active but with progression

Not active and without progression(stable disease)

Lublin FD, et al. Neurology. 2014;83:1-9.

Progressive relapsing MS is no longer considered a distinct disease course .

Progressive MS: 2014/20?? Definitions

Progressive DiseaseAdvanced/Chronic MS

Progressive/Worsening accumulation of disability from

onset(PP)

Progressive/Worsening accumulation of disability after

initial relapsing course

(SP)

Active and with progression/worsening

Active but without progression/worsening

Not active but with progression/worsening

Not active and without progression/worsening(stable disease)

Lublin FD, et al. Neurology. 2014;83:1-9.

Progressive relapsing MS is no longer considered a distinct disease course .

Very low risk

ageplace of residence

outdoor activity / sun exposure / sun screendiet / vitamin D supplements

age of exposure to EBVsmoking

At risk High Risk

Low risk

RIS CIS MS

family historygenetics

sexmonth of birthplace of birth

Unfavourable disease-modifying factorsdynamic risk factorsstatic risk factors

dynamic protective factorsstatic protective factors

MRI / evoked potentials changes

Peripheral immunological changesT-regs (), NK cells, CD8 ()

Clinical disease

In utero childhood Adolescence / early adulthood adulthood

1. Declining Physiology – “peripheral immunological endophenotype”2. Biological disease threshold – “CNS endophenotype”3. Asymptomatic disease – RIS (abnormal MRI and/or evoked

potentials)4. Clinical disease

a. Clinically isolated syndrome (CIS)b. Relapsing MSc. Relapsing secondary progressive MSd. Non-relapsing secondary progressive MS

Favourable disease-modifying factors

protective HLA haplotypes

CNS changes(OCBs and microscopic pathology)

2

3

24b 24c 24d

24a

1

BIO

LOGI

CAL

DEFI

NIT

ION

ENDO

PHEN

OTY

PE

Is there such a thing as therapeutic window?

MRI Lesions

1st clinicalattack

Time (Years)

Asymptomaticdisease

Inflammation


Dise

ase

Seve

rity

SPMSRRMS

1st MRI lesion

Relapses

CISRIS R-SPMS


PPMS

EDSS < 4.0 / ? Age < 40

Disease & Taxonomy

1. When does MS begin?2. When does the progressive phase begin?3. Is MS really 2 or 3 diseases?4. Is there such a thing as therapeutic window?

29

Therapeutic window 5

Asynchronous progressive MS hypothesis

Motor system to legs

Lower limb sensory

BladderTherapeutic window 1



Upper limb sensory

Upper limb motor

Cognition

Vision

Etc.





Therapeutic window 10, etc….

Diagnosis of clinically-apparent progressive MS

Effective DMTs could still target the remaining windows of therapeutic opportunity for individual neurological systems despite some systems have entered the clinically-apparent

progressive phase of the disease

Cerebellar or balance systems

Goodkin et al. Ann Neurol. 1995 Jan;37(1):30-40.

Goodkin et al. Ann Neurol. 1995 Jan;37(1):30-40.

❌❌

✔ ✔

32

Methods and resultsStandard analysis:KM survival curves and Cox model (proportional hazard assumption=HR constant over time)

SPECTRIMS PROMISEHR=0.88 (0.72-1.07), p=0.19 HR=0.88 (0.71-1.07), p=0.18

Slide courtesy of Maria Pia-Sormani

Time dependent analysisAnalysis with a ‘time dependent’ treatment effect :

1. Treatment effect : SPECTRIMS : best time lag= 2.5 years

HR=0.65 (0.43-0.98), p=0.041

Fixed time lag

PROMISE : best time lag= 2 years

HR=0.65 (0.42-0.99), p=0.044


EDSS-dependent time lagEDSS=3-4N=562

EDSS=4.5-6N=678

EDSS=6.5+N=313


Natalizumab in SPMS (ASCEND Study)

Steiner et al. AAN 2016

Ocrelizumab (anti-CD20) in PPMS (ORATORIO STUDY)

Giovannoni et al. ECTRIMS 2016

Ocrelizumab (anti-CD20) in PPMS (ORATORIO STUDY)

Montalban et al. ECTRIMS 2016

Placebon=244

Ocrelizumab 600 mgn=488

Age, yr, mean (SD) 44.4 (8.3) 44.7 (7.9)

Female, n (%) 124 (50.8) 237 (48.6)

Time since symptom onset, yr, mean (SD) 6.1 (3.6) 6.7 (4.0)

Time since diagnosis, yr, mean (SD) 2.8 (3.3) 2.9 (3.2)

MS disease modifying treatment naive, n (%) 214 (87.7) 433 (88.7)

EDSS, mean (SD) 4.7 (1.2) 4.7 (1.2)

MRI findingsGd– lesions, n (%)Number of Gd+ T1 lesions, mean (SD)T2 lesion volume, cm3, mean (SD)

Normalised brain volume, cm3, mean (SD)

183 (75.3%)0.6 (1.6)

10.9 (13.0)11.0 (0.9)

351 (72.5%)1.2 (5.1)

12.7 (15.1)12.8 (0.7)

Classification of MS

Multiple Sclerosis


Health Services

Databasing

Research Personalised Medicine1. Disease

a. Multiple sclerosisb. Classification

2. Research3. Databasing4. Shared-decision making5. Health Services

Objectives

Health Services

NHS1953

Email

SMS

PrivateePortal

Letters

Clinic

GroupClinics

Tele-phone

Skype

Apps

Apps

GroupePortal

BlogDI

SRU

PTIO

N IN

THE

AR

EA O

F SE

RVIC

E DE

VELO

PMEN

T

Michelin Star Service

Fast-food Service

MS Brain Health – a potential ‘tripadvisor’ for MS …

msAdvisor

A quality improvement approach to measure local adoption of the recommendations

Example intervention

Specificintervention




Improve accessto DMTs by…

Contributing factor

Early diagnosis

Aim: maximize lifelong brain health in

people with MS and improve outcomes

Contributing factor

MRI monitoring

Contributing factor

Optimize treatment for each individual

Action effect methodology is iterative; the diagram develops as different stakeholders are

engaged

Engage with a wide range of stakeholders to gain buy-in and to agree on an overall aim, desired outcomes and measure concepts DMT treatment rates

The diagram acts as a ‘road map’ – a starting point for pilot projects in specific healthcare systems

Local application

Agree on the overall aim, aspirations and scope

Agree on factors that contribute to the aim

Interventions are changes made to achieve the aim

Measure concept, are we seeing

improvement in a process/outcome?

Cause/effect arrow

Local application

M M M

M

M

M

M

msAdvisor Barts-MS, Royal London HospitalWhitechapel, London E1 1BB

Overall

Diagnosis

Monitoring

DMTs

Co-morbidities

Education

Relapses

62 reviews

38.6 days

868 MSers

54%

8.3 days

1211 MSers

187 reviews

Contact Staff Services For you search

Conclusions

●Personalised medicine is soft construct relative to precision medicine, which is a harder construct

●Patient focused

●Theoretical construct (ESF - Personalised Medicine for the EU Citizen)

●Need we get our house in order

○ Disease definitions

○ Research & Databasing

○ Shared-decision making

○ Health Services

●Revolution in how we deliver health services to pwMS

personalised medicine ecf

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