MS Doughnut or Bagel ver. 2

Who likes doughnuts?

Gavin Giovannoni Barts and The London

Or do you prefer bagels?

Guidelines for the prescribing of IFN-beta and GA

Fulfil the following 4 criteria:

1. Able to walk independently

2. At least two clinically significant relapses in the last two years

Where possible, the patient’s history of relapses should have been confirmed by neurological examination or from another source e.g. hospital or general practitioner’s records, or by discussion with the patient’s main carer.

3. Adult age group (18 years or older)

no recommendations are possible in the paediatric age group, since trials have not been performed in this cohort.

4. There are no contraindications

Association of British Neurologists Guidelines for the use of Beta Interferons and Glatiramer Acetate in MS, January 2001.

Guidelines for the prescribing of Natalizumab

Natalizumab is recommended as an option for the treatment only of rapidly evolving severe relapsing–remitting multiple sclerosis (RES). RES is defined by two or more disabling relapses in 1 year,

and one or more gadolinium-enhancing lesions on brain magnetic

resonance imaging (MRI) or a significant increase in T2 lesion load

compared with a previous MRI.

1st-line or naïve MSers or 2nd-line (IFN-beta or GA failures)

NICE - Natalizumab for the treatment of adults with highly active relapsing–remitting multiple sclerosis; August 2007.

Definition of a disabling relapse

There is no accepted definition of a disabling relapse; the following is a working definition I proposed after Natalizumab got its license:

“A disabling relapse is a relapse that causes sufficient neurological impairment to impact on the social and/or occupational wellbeing of the MSer, i.e. to affect their pre-relapse or baseline activities of daily living. In other words from the MSer’s perspective, the disability must be of sufficient severity to cause a handicap.

From a physician’s perspective a disabling relapse would typically require treatment with corticosteroids and/or admission to hospital.”

Giovannoni, Personal communication; August 2007.

Guidelines for the prescribing of Fingolimod

Fingolimod is recommended as an option for the treatment of highly active relapsing–remitting multiple sclerosis in adults, only if:

1. they have an unchanged or increased relapse rate or on-going severe relapses compared with the previous year despite treatment with beta interferon, and

2. the manufacturer provides fingolimod with the discount agreed as part of the patient access scheme.

NICE Fingolimod: final appraisal determination document; 16 March 2012 .

The relapsing MS DMT doughnut


Inactive RRMS

CIS

RIS or asymptomatic MS

Suboptimal responders ?

Active RRMS

Highly active RRMS


Inactive RRMS

CIS



Active RRMS

IFNbeta or GA

Highly active RRMS Natalizumab


Inactive RRMS

CIS



Active RRMS

IFNbeta or GA

IFNbeta

Highly active RRMS Fingolimod Natalizumab

Emerging concepts in MS

NEDD; no evidence of detectable disease

TTT; treat-to-target

Treat early

Natural course of disease

Later intervention

Later treatment

Treatment at diagnosis Intervention

at diagnosis

Time Disease Onset

Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFN-1b trial

Goodin et al. Neurology 2012;78:1315-1322.

Any Negative EDSS=6 SPMS Wheelchair

% R

isk R

ela

tive t

o L

ow

Exp

osu

re

Long-term follow-up 16 years

IFN-beta exposure 80% vs. 20%

Goodin et al. PLoS One. 2011;6(11):e22444. Epub 2011 Nov 30.

Establishing long-term efficacy: use of recursive partitioning and propensity score adjustment to estimate outcome in MS

Relationship between early clinical characteristics and long term disability outcomes: 16 year cohort study (follow-up) of the pivotal interferon b-1b trial

Goodin et al. J Neurol Neurosurg Psychiatry. 2012 Mar;83(3):282-7.

100 MSers Who are the responders?

~20% responders

~40% sub-optimal responders

~40% non-responders

vs.

1

2

3

Clinical

MRI

NABs

Relapses

Relapse on IFNβ Therapy Increases Risk of Sustained Disability Progression

Bosca et al. Mult Scler. 2008;14:636-639.

HR SE P Value 95% CI

No relapses (reference=1) 1

One relapse 3.41 1.47 0.005 1.46–7.98

Two or more relapses 4.37 1.74 0.000 1.90–9.57

HR of EDSS Increase in Patients with No Relapses, 1 Relapse, and 2 or More Relapses During the First 2 Years of IFN Treatment

0 20 40 60 80

0

0.25

0.50

0.75

Analysis Time (Months)

No Relapses One Relapse Two or More Relapses

1.00

EDSS

Pro

gres

sio

n

Surv

ival

Pro

bab

ility

HR=hazard ratio; SE=standard error

Relapses and residual deficits

Lublin FD et al. Neurology. 2003;61:1528-1532.

Bermel et al. Ann Neuol 2012; In Press.

Predictors of long-term outcome in MSers treated with interferon beta-a


Predictors of long-term outcome in MSers treated with interferon beta-1a

MRI activity


Predictors of long-term outcome in MSers treated with interferon beta-1a

MRI to monitor treatment response to IFNβ: a meta-analysis

Dobson et al. Submitted 2012.

Study or Subgroup Odds Ratio

IV, Random, 95% CI

Kinkel 2008

Prosperini 2009

Total (95% CI) 9.86 (2.33, 41.70)


IV, Random, 95% CI

Kinkel 2008

Pozzilli 2005

Prosperini 2009

Sormani 2011

Total (95% CI) 2.69 (0.72, 10.04)

0.01 0.1 1 10 100 Disease Less Likely Disease More Likely

One New T2 Lesion

Favors Experimental Favors Control

100 10 1 0.1 0.01

Two or More New T2 Lesions


IV, Random, 95% CI

Kinkel 2008

Rio 2008

Total (95% CI) 5.46 (2.48, 12.04)

MRI to monitor treatment response to IFNβ: a meta-analysis

Dobson et al. Submitted 2012.


IV, Random, 95% CI

Kinkel 2008

Pozzilli 2005

Tomassini 2006

Total (95% CI) 3.34 (1.36, 8.22)

0.01 0.1 1 10 100 Disease Less Likely Disease More Likely

One New Gd+ Lesion

0.01 0.1 1 10 100

Disease Less Likely Disease More Likely

Two or More New Gd+ Lesions

Disease progression

Strongest predictor of disability progression on IFNβ therapy is progression itself

Disease activity during 2 years of treatment and prediction of disability progression* at 6 years

Group Sensitivity (%)

(CI) Specificity (%)

(CI)

A. An increase of at least one EDSS step confirmed at 6 months 85 (64–95) 93 (86–97)

B. Occurrence of any relapse 80 (58–92) 51 (41–61)

C. Occurrence of two or more relapses 45 (26–66) 81 (72–82)

D. A decrease in relapse rate less than 30% compared with 2 years before therapy

40 (22–61) 86 (77–91)

E. A decrease in relapse rate less than 50% compared with 2 years before therapy

40 (–61) 81 (72–88)

F. No decrease or identical relapse rate compared with 2 years before therapy

35 (18–57) 88 (79–93)

G. Definition A or B 90 (70–97) 48 (38–58)

H. Definition A or E 85 (64–95) 76 (66–83)

I. Definition A and B 75 (53–89) 97 (91–99)

J. Definition A and E 40 (22–61) 99 (94–99)

*EDSS score ≥6.0 or increase in at least 3 EDSS steps.

Río J et al. Ann Neurol. 2006;59:344-352.

Relationship between early clinical characteristics and long term disability outcomes: 16 year cohort study (follow-up) of the pivotal interferon b-1b trial

Goodin et al. J Neurol Neurosurg Psychiatry. 2012 Mar;83(3):282-7.

Clinical importance of NAbs against IFNβ RRMSers

*Log-rank test; NAb+=NAb positive; NAb–=NAb negative. Sorensen PS et al. Lancet. 2003;362:1184-1191.

1.0

66 0 6 12 18 24 30 36 42 48 54 60

Time (months)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

Pro

bab

ility

of

Re

mai

nin

g Fr

ee

of

Re

lap

se

Number at Risk NAb+ NAb–

183 355

135 265

95

216

80

182

64

155

45

112

30

179

18 60

11 41

8

24

3

15

Kaplan-Meier Analysis of Time to First Relapse and Proportion of Relapse-Free Patients in NAb+ and NAb– Patients*

NAb– at 12 months NAb+ at 12 months

P=0.0369

Mean change in EDSS

*Log-rank test. Malluchi S et al. Neurology. 2004;62:2031–2037.

0 6 12 18 Months

24 30 36 0

25

50

75

100 P

atie

nts

(%

) w

ith

a S

eco

nd

Re

lap

se NAb–

NAb+

Kaplan-Meier Estimates of Probability of Second Relapse During 3-Year Follow-Up in NAb– and Persistent NAb+ Patients*

P=0.0064

Predictors of long-term clinical response to IFNβ therapy in relapsing MS

Tomassini V et al. J Neurol. 2006;253:287-293.

Variables Odds Ratio 95% CI P Value

Baseline

T1-hypointense lesion load (cm3)

<1.6 1.0

≥1.6 6.8 (2.3, 20.3) <0.001

At 1-year follow-up

Gender

Female 1.0

Male 4.9 (1.5, 16.4) 0.009

NAbs

Absence (-ve) 1.0

Presence (+ve) 7.3 (2.0, 27.1) 0.003

Incidence and significance of anti-natalizumab NAbs Results from AFFIRM and SENTINEL

*P≤0.05 vs Ab– patients; †P=0.66 vs placebo. Calabresi P et al. Neurology. 2007;69:1391-1403.

Placebo NAb–

Transiently NAb+ Persistently NAb+

315 568 20 37

296 550 19 32

283 538 18 26

264 526 16 25

248 506 16 24

240 487 16 22

229 480 15 22

216 470 14 16

208 460 14 16

200 449 14 15

Number at Risk

0 12 24 36 48 60 72 84 96 108 120

Week

0

0.1

0.2

0.3

0.4

0.5

Cu

mu

lati

ve P

rop

ort

ion

of

Pati

en

ts

wit

h S

us

tain

ed

Dis

ab

ilit

y P

rog

res

sio

n

(ED

SS

)

17%

Placebo

NAb–

Transiently NAb+

Persistently NAb+

17%

29%

34%*†

Incidence and significance of anti-natalizumab NAbs Results from AFFIRM and SENTINEL (cont.)

Values are n (%). *P<0.05 vs persistently NAb+; †P<0.01 vs persistently NAb+; ‡P<0.001 vs persistently NAb+. Calabresi P et al. Neurology. 2007;69:1391-1403.

NAb– (n=568)

Transiently NAb+ (n=20)

Persistently NAb+ (n=37)

Natalizumab monotherapy

Headache 4 (24)† 0* 19 (7)

Urticaria <1 (4)‡ 5 (1) 14 (5)

Nausea 1 (8)‡ 0 16 (6)

Rigors <1 (1)‡ 0 11 (4)

Natalizumab add-on therapy (n=515) (n=32) (n=38)

Rigors <1 (1)‡ 0‡ 29 (11)

Nausea 1 (7)‡ 0* 18 (7)

Headache 4 (20)* 3 (1) 13 (5)

Pruritus ≤1 (4)† 3 (1) 11 (4)

Flushing ≤1 (3)‡ 0 13 (5)

Urticaria ≤1 (2)‡ 0 13 (5)

Tachycardia 0‡ 0 11 (4)

Dizziness 3 (15) 0 8 (3)

Pyrexia <1 (3)† 0 8 (3)

Incidence of Common Infusion-Related Adverse Events by Antibody Status in AFFIRM and SENTINEL

vs.

1

2

3

Clinical

MRI

NABs

WWW.MS-RES.ORG

Treat-to-target

Disease activity free

MS Doughnut or Bagel ver. 2

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Transcript of MS Doughnut or Bagel ver. 2