Prognosis of MSHow to communicate it to people with MS

Gavin Giovannoni

Disclosures

I have 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,

Almirall, 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.

Reasoning by analogy

Images courtesy of Professor Gavin Giovannoni

ESRF

end-stage renal failure

Images courtesy of Professor Gavin Giovannoni

Rheumatoid arthritis

End-stage joint disease

Images http://www.hopkinsarthritis.org/arthritis-info/rheumatoid-arthritis/ra-symptoms/

The treatment target in MS is an evolving and moving target

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

OCB-ve

Clinical activity

Focal MRI

activity

Hidden focal and diffuse MRI activity

Microscopic or biochemical pathology

Biomarkers

Early effective treatment

Stroke or brain attack: ‘time really is brain’

Passive Active

Early intervention and long-term prognosis

www.msbrainhealth.org

Giovannoni G, et al. Brain health: Time matters in multiple sclerosis. 2015 Available at www.msbrainhealth.org/report

Incre

asin

g d

isab

ilit

y

Time

Intervention

at diagnosis

Intervention

later

Potential

range of

outcomes

No treatment

Later intervention

Intervention at diagnosis

International policy initiative

www.msbrainhealth.org

DMT, disease-modifying therapy.

Images used with permission from Giovannoni G, et al. Brain health: Time matters in multiple sclerosis. 2015 www.msbrainhealth.org/report. Accessed 26 May 2016.

MS Brain Health vision and aim*

*Defined by MS Brain Health Steering Committee in 2015

Our overarching aim is to encourage the

widespread adoption of a therapeutic strategy

that aims to maximize the lifelong brain health of

every person with MS

Our vision is to create a better future for

people with MS and their families

Expert patient

Expert Patient

‘When acute disease was the primary cause of illness, patients

were generally inexperienced and passive recipients of medical

care. Now that chronic illness has become the principle medical

problem, the patient must become a co-partner in the process’

(Holman & Lorig 2000)

Concordance modelCompliance model

Neurologist decides diagnosis and

treatment

Neurologist’s task is to explain and

instruct

Neurologist’s task is to

comprehend

Successful outcome is compliance

Neurologist and patient negotiate

diagnosis and treatment

Neurologist elicits, explains, persuades

and accommodates

Patient explains, considers and

accommodates

Successful outcome is a negotiated

agreement

Moving from compliance to concordance

requires a culture change

Source: From Compliance to Concordance, 1997 Compliance vs. Adherence

Infographics

Rieckmann et al . Mult Scler Relat Disord 2015 May;4(3):202-18.

Telling it how it is

What is the risk of you not

being treated?

www.ms-res.org

Impact of disability on employment

Kobelt G. Presentation to EMSP, March 7th, 2017; Kobelt G, Mult Scler. 2017 [Epub ahead of print]

European burden of illness study:

Cross sectional study of 16,808 participants, 52% with RRMS, across 16 countries.

100

90

80

70

40

30

10

0

60

0

Pe

rce

nt

(%)

20

50

1.0 2.0 3.0 4.0 5.0 6.0 6.5 7.0 8.0 9.0

94.3 94.6 93.688.3 88.4

81.0

73.9 72.5

64.158.9 59.4

81.776.6

68.4

54.149.0

39.0

29.4 27.5

16.4 14.6

8.2

EDSS score

Patients below retirement age Patients below retirement age, employed or self-employed

Prognostic factors

Prognostic factors

1. Older age of onset (>40 years)

2. Male sex

3. Multifocal onset

4. Efferent system affected

a. Motor/weakness

b. Cerebellar

c. Bladder

5. Relapses

a. Partial or no recovery from initial

relapses

b. High relapse rate in the first 2-yrs (>

2 relapses)

6. Disability after 5 years (EDSS > 3.0)

http://multiple-sclerosis-research.blogspot.com/2014/02/clinic-speak-what-prognostic-group-do.html

7. Abnormal MRI

a. High lesion load (>9 lesions on MRI)

b. Gd-enhancing lesions

c. Posterior fossa lesions

d. Spinal cord lesions

e. Brain atrophy

8. Abnormal evoked potentials

9. Abnormal spinal fluid

a. Oligoclonal IgG bands

b. Raised neurofilament levels

10. Low vitamin D levels

11. Comorbidities

a. Smoker

b. Diabetes

c. Hypertension

d. Obesity

Time from disease onset to EDSS 6*

Pe

rce

nta

ge

of

pa

tie

nts

100

80

60

40

20

0

0 10 20 30 40 50

Time (yrs)

Number of relapses 1st and 2nd year

1

2

>/= 3

Relapses and EDSS

Scalfari A et al. Brain 2010;133:1914–29.

EDSS at 15-year follow-up

Figures reprinted from Bermel R et al. Ann Neurol 2013;73:95–103.

ED

S a

s fo

llow

-up

1

2

Quartile 1

Median 1.5

n=34

Quartile 2

Median 5.5

n=28

Quartile 3

Median 6.0

n=31

Quartile 4

Median 8.0

n=43

4.50

6.50

7.50

10.0

5.50

4.503.50

0.00

1

0

8

6

4

2

-

2

0

MSCRG study:

MRI at baseline,

Year 1 and 2

Assurance study:

Long-term clinical follow-up

Placebo

IM IFN β-1a

30 μg qwk Treatment chosen

By the treating physician

15 years2 years

Gd+

New T2

Relapse

Gd+

New T2

Relapse

8.96 (2.53, 31.65) <0.001

2.89 (0.88, 9.54) 0.080

4.44 (1.43, 13.85) 0.010

1.79 (0.62, 5.16) 0.284

2.62 (0.93, 7.43) 0.069

1.53 (0.56, 4.19) 0.408

Odds ratio of advancing into the

Worst quartile of EDSS change after 15 years

0 10 20 30 401

Early disease

activity*

OR (confidence

interval) p-value

Pla

cebo

IM I

FN

β-1

a

Bermel R et al. Ann Neurol 2013;73:95–103. EDSS, Expanded Disability Status Scale; Gd, gadolinium; IFN, interferon; IM, intramuscular; OR, odds ratio

CIS patients

n=40Healthy controls

n=30

p<0.0001

Deficits in memory, speed

of information processing,

attention and executive

functioning

Patients failing

≥2 cognitive tests

CIS, clinically isolated syndrome

Feuillet L et al. Mult Scler 2007;13:124–7.

Cognition

Brain atrophy occurs across all stages of the disease

De Stefano, et al. Neurology

2010

n= 963 MSers

Poor cognitive function in untreated patients predicts clinically

meaningful disability progression over 2 years

BL PASAT-3 ≤46

(1st tertile)

(n=542)

BL PASAT-3 47–60

(2nd and 3rd tertiles)

(n=1040)

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

BL 12 24 36 48 60 72 84 96 108

Pro

po

rtio

n o

f p

ati

en

ts w

ith

co

nfi

rme

d p

rog

res

sio

n†

Time on study (weeks)Patients at risk

BL PASAT-3 ≤46

BL PASAT-3 47−60

542

1040

372

868

287

768

213

646

484

970

126

454

104

413

76

365

44

256

13

125

Best baseline factor predicting confirmed progression:

Data from placebo arms of four Biogen Phase 3 RRMS trials (AFFIRM, DEFINE, CONFIRM, ADVANCE*)

*AFFIRM, natalizumab vs placebo; DEFINE and CONFIRM, dimethyl fumarate vs placebo; ADVANCE, peginterferon beta-1a vs placebo. †Progression confirmed at 6 months on any of EDSS (≥1 point increase), T25FW, 9HPT, PASAT-3 (≥20% worsening), or visual function (≥10 letter worsening on 2.5%

contrast Sloan letter chart). BL, baseline; 9HPT, 9-hole peg test; PASAT, paced auditory serial addition test; T25FW, timed 25-foot walk; VFT, visual function test.

Raghupathi K, et al. Presented at AAN 2015;P3.211.

Percentage employed

0

None

One

Tw

o

Three

Nu

mb

er

of

tests

failed

10 20 30 40 50 60 70 80

Cognitive impairment can have a major impact on patients‘ lives

Campbell J, et al. Postgrad Med J. 2017;93:143–147.

Rates of employment versus number of tests in the

BICAMS cognitive assessment battery failed, in a cohort of MS patients (n=62)

Even mild cognitive impairment, i.e. failing

one of the battery of tests, results in

significant functional loss, seen here as a

50% decrease in patients’ employment

Cognitive impairment in newly-diagnosed RRMS patients

predicts MS progression over 10 years

NB: Hazard ratios (HR) are based on outcome probability for patients with cognitive impairment relative to those without.

Moccia M et al. Mult Scler. 2016;22:659-667

Results of a retrospective, 10-year study of 155 RRMS patients, comparing presence and absence of cognitive

impairment on the Rao BRB, assessed within 6 months of diagnosis:

First relapse

HR=0.793; p=0.209

Disability

HR=3.183; p<0.001

Progression to SPMS

HR=2.535; p=0.008

1.0

0

0.7

5

0.5

0

0.2

5

0.0

00 2 4 6 8

1

0

1

2

1.0

0

0.7

5

0.5

0

0.2

5

0.0

00 2 4 6 8

1

0

1

2

1.0

0

0.7

5

0.5

0

0.2

5

0.0

00 2 4 6 8

1

0

1

2Time to relapse from MS diagnosis (years) Time to EDSS 4.0 from MS diagnosis (years) Time to secondary progression

from MS diagnosis (years)

No cognitive impairment

Cognitive impairment

No cognitive impairment

Cognitive impairment

No cognitive impairment

Cognitive impairment

Example of serum NfL profile in an MS patient:

NfL tracked with disease activity

• Year 1 to Year 2: high NfL, high disease activity and brain atrophy

• Year 2 to Year 4: low NfL levels, stabilized MRI and brain atrophy

Placebo PEG-IFN

Year 2

EDSS=2 Gd+= 0New T2=48PBVC=-3.11%SDMT-23

Year 4

EDSS=2Gd+ = 0New T2=49PBVC=-4%SDMT=38

Year 3

EDSS=2Gd+ = 0New T2=49PBVC=-2.54%SDMT=39

Year 1

EDSS=0Gd+= 13New T2=28PBVC=-1.34%SDMT=39

a Data from ADVANCE study.

Se

rum

NfL

, p

g/m

L

Year 0 = BL

EDSS=0Gd+= 0SDMT=48

Slide courtesy Rick Rudick, AAN 2018

Prognostic score

Prognostic factors

1. Older age of onset (>40 years)

2. Male sex

3. Multifocal onset

4. Efferent system affected

a. Motor/weakness

b. Cerebellar

c. Bladder

5. Relapses

a. Partial or no recovery from initial

relapses

b. High relapse rate in the first 2-yrs (>

2 relapses)

6. Disability after 5 years (EDSS > 3.0)

http://multiple-sclerosis-research.blogspot.com/2014/02/clinic-speak-what-prognostic-group-do.html

7. Abnormal MRI

a. High lesion load (>9 lesions on MRI)

b. Gd-enhancing lesions

c. Posterior fossa lesions

d. Spinal cord lesions

e. Brain atrophy

8. Abnormal evoked potentials

9. Abnormal spinal fluid

a. Oligoclonal IgG bands

b. Raised neurofilament levels

10. Low vitamin D levels

11. Comorbidities

a. Smoker

b. Diabetes

c. Hypertension

d. Obesity

Prognostic factors

1. Older age of onset (>40 years) ✓

2. Male sex ✓

3. Multifocal onset ✓

4. Efferent system affected

a. Motor/weakness ✓

b. Cerebellar ✓

c. Bladder ✓

5. Relapses

a. Partial or no recovery from initial

relapses ✓

b. High relapse rate in the first 2-yrs (>

2 relapses) ✓

6. Disability after 5 years (EDSS > 3.0) ✓

http://multiple-sclerosis-research.blogspot.com/2014/02/clinic-speak-what-prognostic-group-do.html

7. Abnormal MRI

a. High lesion load (>9 lesions on MRI) ✓

b. Gd-enhancing lesions ✓

c. Posterior fossa lesions ✓

d. Spinal cord lesions ✓

e. Brain atrophy ✓

8. Abnormal evoked potentials ✓

9. Abnormal spinal fluid

a. Oligoclonal IgG bands ✓

b. Raised neurofilament levels ✓

10. Low vitamin D levels ✓

11. Comorbidities

a. Smoker ✓

b. Diabetes ✓

c. Hypertension ✓

d. Obesity ✓

? / 22 factors

Prognostic factors

1. Older age of onset (>40 years) ✓

2. Male sex ✓

3. Multifocal onset ✓

4. Efferent system affected

a. Motor/weakness ✓

b. Cerebellar ✓

c. Bladder ✓

5. Relapses

a. Partial or no recovery from initial

relapses ✓

b. High relapse rate in the first 2-yrs (>

2 relapses) ✓

6. Disability after 5 years (EDSS > 3.0) ✓

http://multiple-sclerosis-research.blogspot.com/2014/02/clinic-speak-what-prognostic-group-do.html

7. Abnormal MRI

a. High lesion load (>9 lesions on MRI) ✓

b. Gd-enhancing lesions ✓

c. Posterior fossa lesions ✓

d. Spinal cord lesions ✓

e. Brain atrophy ✓

8. Abnormal evoked potentials ✓

9. Abnormal spinal fluid

a. Oligoclonal IgG bands ✓

b. Raised neurofilament levels ✓

10. Low vitamin D levels ✓

11. Comorbidities

a. Smoker ✓

b. Diabetes ✓

c. Hypertension ✓

d. Obesity ✓

? / 22 factors

< 30% - Good

30-70% - Intermediate

> 70% - Poor

Aim of treatment

Good

Indeterminate

Poor

time Aim of treatment

Predicting a DMT response

100 MSers

Who will be

the DMT

responders?

20:80

?

✓

NEDA

MEDA

EDA

EDA = evidence of disease activity (clinical); MEDA = minimal evidence of disease activity (MRI); NEDA = no evidence of disease activity (no clinical and MRI activity)

Hypothetical responder rates on

a low efficacy DMT

40:60

?

✓

NEDA

MEDA

EDA

EDA = evidence of disease activity (clinical); MEDA = minimal evidence of disease activity (MRI); NEDA = no evidence of disease activity (no clinical and MRI activity)

Hypothetical responder rates on

a moderate efficacy DMT

80:20

?

✓

NEDA

MEDA

EDA

EDA = evidence of disease activity (clinical); MEDA = minimal evidence of disease activity (MRI); NEDA = no evidence of disease activity (no clinical and MRI activity)

Hypothetical responder rates on

a very high efficacy DMT

20:80

40:60

80:20

At present it is not possible to

predict who will respond to a

particular DMT.

You simply increase your odds

of being a responder with more

efficacious DMTs Moderate efficacy DMT

Low efficacy DMT

Very high efficacy DMT

Treatment ladder vs. flipping the pyramid

Active

Active

Active HDA

IFN beta

Teri

GA

DMF

Alem Ocre

Alem, alemtuzumab; Clad, cladribine tablets; DMF, dimethyl fumarate; Fingo, fingolimod; HDA, high disease activity; GA, glatiramer acetate; *HSCT, hematopoietic

stem cell transplantation; IFN beta, interferon-beta; Mitox, Mitoxantrone; Nz, natalizumab; Ocre, ocrelizumab; RES, rapidly-evolving severe; Teri, teriflunomide

NHS treatment ladder

RES Nz Clad

HSCT*

RES

Fingo Clad

Alem

Nz

Level 1

Level 2

Level 3

Ocre

HDA Clad

HDA

RES

Fingo Clad

Alem

Nz

Ocre

Mitox

Mitox HSCT

Nz/Az/Ocr

Fingo/Clad

IFN-𝛃/GA/Teri/DMFActive

Rapidly-evolving severe

NEDA - 1 & 2Clinical activity

NEDA-3Focal MRI activity

NEDA-4/5Brain atrophy / CSF-NFL levels

Nz/Az/Ocr/Fingo/Clad

Conventional step-care‘Treatment Ladder’

Rapid escalation‘Treatment Escalator’

Early top-down‘Flipping the Pyramid’

NEDA = no evident disease activity; NEDA-2 = clinical only (relapse-free and progression free); NEDA-3 = clinical and focal MRI activity; NEDA-4/5 = clinical and focal MRI activity free and normalising brain atrophy loss & normalisation of CSF neurofilament levels. IFN-𝛃 = interferon-beta; GA = glatiramer acetate; Teri = teriflunomide; DMF = dimethyl fumarate; Fingo = fingolimod; Nz = natalizumab; Az = alemtuzumab; Dac = daclizumab, Clad = oral cladribine, Ocr = ocrelizumab

Fingo/CladHighly-active

MS Disease Activity

Inactive

Therapeutic approaches

Therapeutic targets

Different therapeutic approaches to the use of disease-modifying therapies in the treatment of relapsing forms of MS

Nz/Az/Ocr

Watchful waiting

IFN-𝛃/GA/Teri/DMF

Giovannoni G. Curr Opin Neurol. 2018 Jun;31(3):233-243.

Benefits vs. Risks

Benefits of treatment Risks of treatment

Benefits of treatment Risks of treatment

Risks of untreated or

undertreated MS

Kleinschmidt-DeMasters,et al. N Engl J Med. 2005 Jul 28;353(4):369-74.

Infection (PML) complicating treatment with natalizumab

Benefits of treatment Risks of treatment

Risks of untreated or

undertreated MSDerisking DMTs

Conclusions

Conclusions

● Educate your patients; help them become experts

● MS is a bad disease and given time it will cause disability in the majority of patients

○ It is very important to communicate this patients

● Cognitive impairment is common and occurs early

● Treat early and effectively to preserve brain

● Treat to a target

○ NEDA and beyond

● Rapid escalation and flipping the pyramid

● Important to understand how to de-risk DMTs

Thank you