Sequencing of DMTs in Clinical Practice

Sequencing DMTs in Clinical Practice

Gavin Giovannoni Blizard Institute, Barts and The London School of Medicine

December 2014

Disclosures

Over the last 15 years 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, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals.

Professor Giovannoni would like to acknowledge and thank Biogen-Idec for making available data slides on daclizumab for this presentation. He would also like to thank numerous colleagues for providing him with data and/or slides for this, and other, presentations.

Professor Giovannoni’s tour to Canada has been kindly sponsored by Biogen-Idec, therefore please interpret anything he says about Biogen-Idec’s products in this context.

This presentation has been designed and prepared by Professor Giovannoni with no input from any other parties.

IFNbeta

GA

Teri

DMF Fingo

Nz

Az

Treatment Complexity

2014

7 IFNbeta

GA

Teri

DMF

Fingo Nz

Az

Dac

Anti-CD20

2016

9

Copaxone-20

Copaxone-40 Synthon

IFNbeta

GA

Teri

DMF Fingo

Nz

Az

Treatment Complexity

2014

7 IFNbeta

GA

Teri

DMF

Fingo Nz

Az

Dac

Anti-CD20

2016

9

Betaferon

Rebif

Avonex Extavia

Plegridy

What is active MS?

2001 Clinical

2009 Clinical and MRI

2014 Clinical or MRI

Inactive MS: no relapses or MRI activity in the last 24 months

Active MS: relapses in the last 12 or 24 months and/or MRI activity in the last 12 months

Highly active MS: relapses in the last 12 months and MRI activity in the last 12 months

Rapidly-evolving severe MS (RES); two disabling attacks in a 12

month period and MRI evidence of activity during this period.

What is active MS?

2001 Clinical

2009 Clinical and MRI

2014 Clinical or MRI

Inactive MS: no relapses or MRI activity in the last 24 months (NEDA)

Active MS: relapses in the last 12 or 24 months and/or MRI activity in the last 12 months

Highly active MS: relapses in the last 12 months and MRI activity in the last 12 months

Rapidly-evolving severe MS (RES); two disabling attacks

in a 12 month period and MRI evidence of activity

during this period.

IFNbeta

GA

Teri

DMF

Treatment Ladder

DMF

Fingo

Nz Az

100 MSers

Who are the

responders?

?

20:80

?

40:60

Natalizumab STRATA: stable EDSS scores for up to 5 years

*P<0.0001

Kappos L et al. Presented at ECTRIMS; October 10–13, 2012; Lyon, France P520.

1 Year 2 Years 3 Years 4 Years 5 Years

Cessation/

Treatment Gap* Original Placebo

Original Natalizumab

Original Placebo – Now on Natalizumab

Mean

ED

SS

Sco

re

n = 380 707 381 707 280 552 385 709 274 569 230 479 205 462 194 427 174 393

13

?

80:20

NEDA is a sensitive outcome

1.87

5.29

2.75

2.92

3.41

1.64

2.29

0 1 2 3 4 5 6

Dimethyl fumarate (DEFINE)

Natalizumab (AFFIRM)

Cladribine (CLARITY)

Fingolimod (FREEDOMS)

sc IFN β-1a (DoF)

Teriflunomide (TEMSO)

Alemtuzumab (CARE MS II)

Increase in proportion of NEDA patients relative to comparator

Patients with RRMS over 2 years. Increase in proportion of patients with NEDA versus placebo (except CARE MS II)

All data from post hoc analyses of randomized controlled trials in patients with RRMS. Table adapted from Bevan CJ and Cree BA. JAMA Neurol 2014;71:269-70, with the exception of: TEMSO. Freedman et al. Neurology 2012;78 [Meeting

Abstract s 1]: PD5.007; sc IFN b1-a sc. Data on file; CARE MS II. Coles AJ et al. Lancet 2012;380:1829-39

versus sc IFN b-1a

Slide courtesy Prof. Mark Freedman, EFNS-ENS Istanbul 2014

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

MS Iceberg

Clinical activity

Focal MRI activity

Hidden focal and diffuse MRI activity

Microscopic or biochemical pathology

Biomarkers

Control Multiple sclerosis

Slide courtesy of Dr Klaus Schmierer

Brain atrophy occurs across all stages of the disease

De Stefano, et al. Neurology 2010

n= 963 MSers

Association of MRI metrics and cognitive impairment in radiologically isolated syndromes

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

Treatment effect on disability predicted by effect on T2-lesion load and brain atrophy

Meta-analysis of treatment effect on EDSS worsening (y) vs effects on MRI lesions

and brain atrophy, individually or combined, in 13 placebo-controlled RRMS trials

(13,500 patients)

Sormani MP et al. Ann Neurol. 2014;75:43-49.

• Post-hoc analysis of a pivotal clinical trial of IFN β-1a IM1

• Treatment with IFN β-1a IM resulted in a 55% reduction in brain atrophy vs. placebo during the second year of a clinical trial (N = 140)

• Analysis of the MRI cohort of the European IFN β-1a IM dose comparison study2

• Derived from a double-dose study; all patients on-treatment; modelled from pre-treatment rate

IFN β-1a IM

BPF, brain parenchymal fraction; IFN β, beta-interferon; IM, intramuscular; MRI, magnetic resonance imaging; n.s., not significant. 1. Rudick RA, et al. Neurology 1999; 53:1698−1704; 2. Hardmeier M, et al. Neurology 2005; 64:236−240.

–1.06% per year

–0.33% per year

Treatment initiation

Month

0.795

0.800

0.805

0.810

0.815

0.820

0.825

0.830

–3 0 3 6 9 12 18 24 30 36 21 15 27 33

BP

F

p < 0.01

n.s.

Year 1

Year 2

Year 3

Month 4−12

Baseline− Month 4

p < 0.05

p < 0.01

n.s.

–1.6

–1.4

–1.2

–1.0

–0.8

–0.6

–0.4

0.0

–0.2

Annual MRI group (n = 368)

Frequent MRI subgroup (n = 138)

Re

lati

ve B

PF

chan

ge (

%)

–0.482% (+/ –0.58)

–0.228% (+/ –0.73)

–0.348% (+/ –0.61)

–0.393% (+/ –0.58)

–0.686% (+/-0.79)

–0.377% (+/-0.77)

–0.378% (+/-0.73)

TEMSO: 2-year, randomized, placebo-controlled Phase III trial of teriflunomide in patients with RMS (N = 1,088)

Change from baseline in white matter volume

Teriflunomide: white matter atrophy

RMS, relapsing MS. Wolinsky JS, et al. Mult Scler 2013; 19:1310−1319.

• Whole brain atrophy: − no significant effect

• Grey matter atrophy:

− no significant effect

Me

an ±

SE

chan

ge

fro

m b

ase

line

(m

l)

Week

Placebo Teriflunomide 7 mg Teriflunomide 14 mg

2.4

0.8

–0.8

–2.4

–4.0

–5.6

0 24 48 72 108

p = 0.0002

p = 0.0609

No. of patients

Placebo 358 329 309 270 256

7 mg 359 339 301 273 262

14 mg 355 328 293 273 260

Dimethyl fumarate

DEFINE: 2-year, randomized, placebo-controlled study of DMF in patients with RRMS (N = 1,237)1

CONFIRM: 2-year, randomized, placebo-controlled active reference (GA) comparator study of DMF in patients with RRMS (N = 1,430)2

BID, twice daily; DMF, dimethyl fumarate; TID, three times daily. 1. Arnold DL, et al. AAN 2012. Abstract IN3-2.002; 2. Miller D, et al. ENS 2012. O259.

Week 24−Year 2

−30% vs. placebo (p = 0.02)

−17% vs. placebo (p = 0.2478)

• Significant reduction in brain volume loss vs. placebo with DMF BID but not TID

• No significant reduction in brain volume loss vs. placebo with both doses

−6% vs. placebo

(p = 0.831)

−3% vs. placebo

(p = 0.562)

−16% vs. placebo

(p = 0.706)

Week 24−Year 2

Me

dia

n c

han

ge

in w

ho

le b

rain

vo

lum

e (

%)

Me

dia

n c

han

ge

in w

ho

le b

rain

vo

lum

e (

%)

-1.0%

-0.8%

-0.6%

-0.4%

-0.2%

0.0% Years 0-2

-0.82%

-0.80%

P=0.822†

Placebo (N=315) Natalizumab (N=627)

Year 0-1* Year 1-2

-0.40%

-0.56%

-0.43%

-0.24%

P=0.004†

P=0.002†

†Difference between treatments; ‡Change from baseline; Miller DH et al. Neurology 2007;68:1390-1401.

AFFIRM Study: natalizumab and brain atrophy

Mean

(S

E)

perc

en

tag

e c

han

ge i

n B

PF

Brain atrophy in natalizumab-treated patients: 3-year follow-up

Sastre-Garriga et al. MSJ 2014.

-0.6%

-1.4%

-0.1% -0.5%

-0.7%

-0.2%

Reduction in brain atrophy on alemtuzumab

• In all three studies: PBVC assessed for all patients, prospectively, using the SIENA method • Fingolimod significantly reduced brain volume loss over 2 years vs. placebo

• These reductions were observed after 6 months (first post-baseline scan) • Fingolimod significantly reduced brain volume loss over 1 year vs. IFN β-1a IM

Atrophy data from three fingolimod trials

SIENA, Structural Image Evaluation, using Normalisation, of Atrophy. ITT population with evaluable MRI images at baseline and end of core study phase (Month 24). p values are for comparisons over Months 0–6, Months 0–12, Months 0–24. TRANSFORMS: *** p < 0.001 vs. IFN β-1a IM. Wilcoxon rank sum test; FREEDOMS/FREEDOMS II: * p < 0.05; ** p < 0.01; *** p < 0.001 vs. placebo. Rank ANCOVA adjusted for treatment, region and baseline normalized brain volume. 1. Cohen JA, et al. N Engl J Med 2010; 362:402–415; 2. Kappos L, et al. N Engl J Med 2010; 362:387–401; 3. Radue EW, et al. ECTRIMS 2012. P724.

Me

an P

BV

C f

rom

bas

elin

e

TRANSFORMS1

Time (months)

−32%

reduction

0.0

–0.4

–0.6

–1.4

–0.2

–0.8

–1.2

–1.0

0 24 12

*** n = 429

n = 431

0.0

–0.4

–0.6

–1.4

–0.2

–0.8

–1.2

–1.0

0 24 12 6

FREEDOMS2

Time (months)

−35%

reduction

*

**

***

n = 357

n = 331

0.0

–0.4

–0.6

–1.4

–0.2

–0.8

–1.2

–1.0

0 24 12 6

FREEDOMS II3

Time (months)

−33%

reduction

* ***

*** n = 358

n = 355

Placebo Fingolimod 0.5 mg IFN β-1a IM

• For all annual BVL thresholds, significantly more NEDA-4 patients were in the fingolimod-treated group than in the placebo group

Results: NEDA-4 by Annual BVL Thresholds

aORs were derived from logistic regression of freedom from disease activity on treatment.

Kappos et al. ACTRIMS/ECTRIMS 2014. FC1.5

80% of subjects fail treatment on this criteria

Overview DMTs and brain atrophy

IV, intravenous.

Therapy Administration Reduction in PBVC

IFN β/GA SC IM

IFN β-1a IM: positive effect Year 2

Teriflunomide Oral Not significant

DMF Oral −30% (for BID in DEFINE); not significant for TID Not significant for both doses in CONFIRM

Fingolimod Oral –35% (FREEDOMS); –33% (FREEDOMS II); –32% (TRANSFORMS)

Natalizumab IV Significant in year 2

Alemtuzumab IV –42% (naive vs. IFN); –24% (previously treated vs. IFN)

Residual deficits: • Walking distance >500m

• Unable to run

• Exercise induces intermittent

sensory symptoms in L arm

• Mild urinary frequency

17-yr girl, myelitis

Jun-2000

1st-yr University

L-optic neuritis

Feb-2001

clumsy

left hand

Jan -2002

pins & needles

in legs

Oct-2003

R optic neuritis

Mar-2004

Brainstem

syndrome;

diplopia and

ataxia

Dec 2007

Cervical cord

relapse

weak L arm

with pain

Jan 2008

Bladder

dysfunction

depression,

anxiety and

fatigue

Reduced

mobility

Mild urinary frequency

No depression ,anxiety

or fatigue

Fully mobile

NEDA (no evident disease activity)

Feb-2008 to May-2014

IFN-beta

Feb-2001

Natalizumab

Jan-2008

ED

SS

IFN-beta Natalizumab Jun-2000 May-2014

6.0

3.5 3.5

MRI – progressive brain atrophy

Dec 2007 Jul 2010 Jul 2013

Is this patient in long-term remission?

No evidence of disease activity: NEDA-4

Gd, gadolinium. 1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et al. Lancet Neurol 2011; 10:329–337.

Treat-2-target

No evidence of disease activity defined as:1,2

× No relapses

× No sustained disability progression

× No MRI activity

× No new or enlarging T2 lesions

× No Gd-enhancing lesions

How do we add a brain atrophy metric to our definition of NEDA?

Normalisation of brain atrophy rates

Other discriminators

1. Safety (risk:benefit)

2. Tolerability

3. Adherence

4. Monitoring

5. Pregnancy

6. Regional / Cultural influences

7. Cost

8. Marketing

T2T-NEDA-ZeTo

T2T = treating-to-target; NEDA = no evident disease activity; ZeTo = zero tolerance

Choose therapy

A B C

Define the individual’s MS

Treatment failure?

• Patient’s preferences? • Your choice?

Individual measures: • Evidence of disease activity? • Tolerability/safety? • Adherence? • Drug or inhibitory markers? • NABs

Monitoring

• MS prognosis • Life style and goals • Shared goals for therapy

Rebaseline

Rebaseline: • IFNβ, natalizumab, fingolimod,

teriflunomide, DMF=3-6 months • Glatiramer acetate=9 months • Alemtuzumab=24 months

DMF, dimethyl fumarate.

Choose a therapeutic strategy

Maintenance-escalation Induction

Choose therapy

X Z

Rebaseline

Monitoring

Initiate or Switch or Escalate Rx Complete course / Re-treat

Breakthrough disease

Y


No Yes Yes

• Only one licensed induction therapy at present

Choosing a therapeutic strategy

Maintenance therapies

• Continuous treatment

• Low to very high efficacy

• Reversible

• Perceived to be lower risk

• Examples • Laquinimod, GA, IFN-beta, teriflunomide, BG12,

fingolimod, natalizumab, daclizumab

• Breakthrough disease • Suboptimal or failure to respond

• NEDA reliable metric for efficacy

• Rebound activity • Highly likely

• Can be life threatening

• Pregnancy • Contra-indicated

• No potential for a cure • Rebound

• SPMS & progressive brain atrophy

Induction therapies

• Short-courses or pulsed therapy

• Very high efficacy

• Irreversible

• Perceived to be higher risk

• Examples • Mitoxantrone, cladribine, alemtuzumab, anti-

CD20 (?), BMT

• Breakthrough disease • Marker for retreatment

• NEDA unreliable to assess efficacy

• Rebound activity • Less likely

• Unlikely to be life-threatening

• Pregnancy • Strategy of choice

• Potentially curative • 15-20 year experiment

• BMT, alemtuzumab, cladribine

T2T-NEDA-ZeTo


Choose therapy

A B C


Treatment failure?



Monitoring


Rebaseline






Choose therapy

X Z

Rebaseline

Monitoring



Y


No Yes Yes


IFNbeta

GA

Teri

DMF

Treatment Ladder

DMF

Fingo

Nz Az

Time is brain

Natural course of disease

Later intervention

Later treatment

Treatment at diagnosis Intervention

at diagnosis

Time Disease Onset

Dis

abili

ty

Time is brain

Escalation to natalizumab is more effective than switching between IFN/GA

0

25

50

75

100

% P

ati

en

ts

Escalate to Natalizumab, n=106

Switch Between IFN/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).

*There were no differences at 12 month between the two groups in proportions of patients free from relapse, disability progression, MRI

activity, and combined activity.

Prosperini L et al. Mult Scler. 2012;18:64-71.

No EDSS

Progression

No MRI

Activity

Disease

Activity Free

P<0.0001 P=0.0003 P<0.0001

51

36

51

21

83

67 77

59

No

Relapses

P<0.0045

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

CO-CZ-0056l

Real-world comparative effectiveness of Fingolimod and Interferon/Glatiramer therapies in a switch population using

propensity-matched data from MSBase

p=0.019

0.00

0.25

0.50

0.75

1.00

Pro

porti

on o

f pat

ient

s N

OT

rela

psed

0 2 4 6 8 10 12Months since baseline

FINGOLIMOD IFN_COP

Time to first relapse on treatment by treatment arm within first 12 months of switch

p=0.000007

0.00

0.25

0.50

0.75

1.00

Prop

ortio

n of

pat

ient

s N

OT

disc

ontin

ued

0 2 4 6 8 10 12Months since baseline

FINGOLIMOD IFN_COP

Time to treatment discontinuation by treatment arm within first 12 months of switch

Mul t ip le Sc le ros is da taBase Spelman et al. ECTRIMS 2013

Conclusions: In general once on 1st-line/lower-tier therapy

TOP: earlier natalizumab treatment favours annualised relapse rate outcomes

P values from a negative binomial regression model adjusted for gender, baseline EDSS score (<3.0 vs ≥3.0l), relapse status in the prior

year (≤1 vs >1), prior DMT use (<3 vs ≥3), disease duration (<8 vs ≥8 years), and treatment duration (≥3 vs <3 years), except for the factor

of interest. Error bars represent 95% CIs.

DMT=disease-modifying therapy; CI=confidence interval.

Wiendl et al. Presented at ENS; June 8–11, 2013; Barcelona, Spain,. P372.

NEDA outcomes with alemtuzumab: 3-year follow-up of the CARE-MS studies

MRI, magnetic resonance image; CI, confidence interval.

Adapted from Havrdova E et al. Presented on ACTRIMS/ECTRIMS, 2014, FC1.4.

38 46 50

67 64

0

20

40

60

80

100

Year 1 Year 2 Year 3

Pro

po

rtio

n o

f

pati

en

ts, %

(9

5%

CI)

↑32.2% P=0.0062

↑45.8% P<0.0001

CARE-MS I: NEDA by year

SC IFNB-1a

ALEM 12 mg

174

369

170

356

—

349

SC IFNB-1a

ALEM 12 mg

187

405

173

434

—

393

27 31

44

56 55

0

20

40

60

80

100

Year 1 Year 2 Year 3

Pro

po

rtio

n o

f

pa

tie

nts

, %

(9

5%

CI)

↑61.2% P<0.0001

CARE-MS II: NEDA by year

↑84.3% P<0.0001

ECTRIMS 2013

TEMSO & TOWER: Evaluation of the Effect of Teriflunomide in Subgroups Defined by Prior Treatment (Pooled Analyses)

Adjusted ARR by Prior Treatment Disability Progression by Prior Treatment

ARR, annualized relapse rate; DMT, disease-modifying therapy; RRMS, relapsing-remitting MS. Adapted from Freedman M et al. Presented on ACTRIMS/ECTRIMS, 2014, P046.

An

nu

aliz

ed r

elap

se r

ate

Pro

bab

ility

of

d

isab

ility

pro

gres

sio

n

0.423 0.464 0.303 0.463 0.536 0.329 0.794 0.641 0.472 0.0

0.2

0.4

0.6

0.8

1.0

>1 Prior DMT 1 Prior DMT No Prior DMT

0.072 0.201 0.178 0.218 0.345 0.176 0.298 0.299 0.238 0.0

0.1

0.2

0.3

0.4

>1 Prior DMT 1 Prior DMT No Prior DMT

Teriflunomide 14 mg Teriflunomide 7 mg Placebo

46.7%

41.6% 27.7%

16.4% 35.9%

30.2%

78.6%

33.4%

46.6%

5.0%

17.4%

20.8%

Patients (n) 41 32 36 189 193 192 498 547 523 Patients (n) 41 32 36 189 193 192 498 547 523

Post hoc analysis of pooled data of ARR and 12-week confirmed disability progression conducted on patient subgroups defined by prior MS therapy

T2T-NEDA-ZeTo


Choose therapy

A B C


Treatment failure?



Monitoring


Rebaseline






Choose therapy

X Z

Rebaseline

Monitoring



Y


No Yes Yes


Natalizumab • Continuous treatment (monthly infusions)

• Very high efficacy; high NEDA rates and significant proportion of treated subjects improve.

• Prevents end-organ damage (reduced brain atrophy yr-2)

• Reversible treatment effect

• Infusion reactions uncommon

• No short-term generalised immunosuppression

• Reduced immune surveillance increases risk of CNS infections; in particular PML if JCV-seropositive

• Breakthrough disease

• Re-baseline at 3-6 months

• Neutralizing antibodies to natalizumab reduce efficacy and cause infusion reactions

• Suboptimal or failure to respond

• NEDA reliable metric for efficacy

• Rebound activity

• Highly likely, can be life threatening

• Pregnancy

• Not recommended, natalizumab crosses placenta and has transient effects in baby

• No secondary autoimmunity

• No obvious secondary malignancy risk

• Monitoring: yes, blood and liver function tests early on, anti-natalizumab antibodies, JCV serology and annual MRI

• No potential for a cure

• Rebound

Alemtuzumab • Short-course pulsed therapy (2-5 annual cycles of treatment)

• Very high efficacy; significant proportion of treated subjects improve. Reported NEDA rates low, but not measured in correct epoch

• Prevents end-organ damage (reduced brain atrophy yr-2)

• Irreversible treatment effect

• Infusion reactions the norm

• Short-term generalised immunosuppression (8-12 weeks post infusion)

• Low risk of CNS and other infections after immune system reconstitution

• Breakthrough disease

• Re-baseline at 24 months

• Antibodies to alemtuzumab are transient and don’t appear to inhibit activity of drug

• Marker for retreatment

• NEDA unreliable to assess efficacy

• Rebound activity

• Less likely, unlikely to be life-threatening

• Pregnancy

• Fine once immune system reconstituted

• Potential for autoantibodies to cross placenta, for example neonatal hyperthyroidism

• Secondary autoimmunity; ~50% of patients with long-term follow-up - mainly thyroid related.

• Potential, but undefined, secondary malignancy risk

• Monitoring: yes, monthly blood and urine tests for secondary autoimmunity and annual MRI

• Potentially curative

• Long-term remission established in about 50% of treated patients

• Ongoing 15-20 year experiment, analogous to BMT

NEDA is a sensitive outcome

1.87

5.29

2.75

2.92

3.41

1.64

2.29

0 1 2 3 4 5 6

Dimethyl fumarate (DEFINE)

Natalizumab (AFFIRM)

Cladribine (CLARITY)

Fingolimod (FREEDOMS)

sc IFN β-1a (DoF)

Teriflunomide (TEMSO)

Alemtuzumab (CARE MS II)

Increase in proportion of NEDA patients relative to comparator

Patients with RRMS over 2 years. Increase in proportion of patients with NEDA versus placebo (except CARE MS II)

All data from post hoc analyses of randomized controlled trials in patients with RRMS. Table adapted from Bevan CJ and Cree BA. JAMA Neurol 2014;71:269-70, with the exception of: TEMSO. Freedman et al. Neurology 2012;78 [Meeting

Abstract s 1]: PD5.007; sc IFN b1-a sc. Data on file; CARE MS II. Coles AJ et al. Lancet 2012;380:1829-39

versus sc IFN b-1a

Slide courtesy Prof. Mark Freedman, EFNS-ENS Istanbul 2014

REBOUND AFTER NATALIZUMAB WITHDRAWAL

Rigau et al. Neurology. 2012 Nov 27;79(22):2214-6.

Case study

Question: “Prof G I have had 33 natalizumab infusions and I have just found out that I am JCV seropositive with an antibody index of 3.2. What should I do?”

17% 85%

“The power of an infographic……less is more.”

>1,000,000 SlideShare views

www.clinicspeak.com

Truer risk of PML = Number or cases of PML

Number of JCV+ve exposed Msers**

Underestimate of the risk of PML

Number or cases of PML

Number of exposed MSers (JCV+ve & JCV-ve)*

=

* Please note this denominator is changing over time with a greater proportion of exposed MSers being JCV-ve; this will have the effect of under-estimating the risk of PML.

** This denominator is also changing over time by getting relatively smaller as the number of JCV+ve MSers stop natalizumab. Despite this this ratio will provide a more accurate estimate of the risk of getting PML.

What is the true PML risk?

Natalizumab Alemtuzumab

Asymptomatic PML? LP-JCV DNA & MRI

Option 1: Immediate switch (high risk if carry-over PML develops)

Natalizumab Alemtuzumab Oral bridging agent (Teriflunomide, DMF or Fingolimod)

Asymptomatic PML? LP-JCV DNA & MRI

Rebaseline MRI

Option 3: Bridging (low risk; mainly related to using a low efficacy bridging agent and using alemtuzumab after the bridging agent)

6-12 MONTHS

Natalizumab Alemtuzumab

Rebaseline MRI **

3-6 MONTH WASHOUT

Asymptomatic PML?* LP-JCV DNA & MRI

Option 2: Washout (intermediate risk; mainly related to rebound of MS disease activity)

* For this option the shorter the washout the more important the screen for asymptomatic PML becomes. ** PML screening and baseline MRI studies are don’t use the same types of scans hence the need for both.

Switching from natalizumab to alemtuzumab

MS disease activity in RESTORE: a randomized 24-week natalizumab treatment interruption study

Fox et al. Neurology 2014;82:1491–1498.

Switching from natalizumab to fingolimod: a randomized, placebo-controlled study of patients with RRMS

Kappos et al. In Press 2014

Fingolimod after natalizumab and the risk of short-term relapse

Jokubaitis et al. Neurology 2014;82:1204–1211.

ACTRIMS-ECTRIMS 2014

Fingolimod Alemtuzumab

Only treat with alemtuzumab once lymphocyte counts normalize*

2 to 6 12 MONTH WASHOUT

Option 2: Washout (intermediate risk; mainly related to rebound of MS disease activity)

* What constitutes a normal level post-fingolimod needs to be defined; I would be reluctant to give alemtuzumab to anyone with a total lymphocyte count below 1.0x109 .

Fingolimod Alemtuzumab

Option 1: Immediate switch (high-risk if persistent lymphopaenia occurs)

Treat with alemtuzumab before lymphocyte counts normalize

Fingolimod Alemtuzumab Bridging agent (IFN-beta, GA, Teriflunomide or DMF)

Only treat with alemtuzumab once lymphocyte counts normalize*

Option 3: Bridging (low risk; mainly related to MS rebound as a result of using a low efficacy bridging agent after fingolimod)

3-12 MONTHS

* What constitutes a normal level in this situation needs to be defined; I would be reluctant to give alemtuzumab to anyone with a total lymphocyte count below 1.0x109 .

Switching from fingolimod to alemtuzumab

Reconstitution of circulating lymphocyte counts in FTY720-

treated MS patients

Johnson et al. Clinical Immunology (2010) 137, 15–20

The incidence and significance of anti-natalizumab antibodies Results from AFFIRM and SENTINEL

Calebresi & Giovannoni, et al. Neurology 2007;69:1391–1403.

Pregnancy

Case Study

• 30 year old woman RRMS diagnosed 2001

• Two relapses, EDSS 1.0

• Started on natalizumab 300mg ivi monthly as part of a clinical trial

• NEDA (no evident disease activity) on natalizumab x 8 years

• Now wants to start a family; would you stop natalizumab?

Case 3

• 30 year old woman RRMS diagnosed 2001

• Two relapses, EDSS 1.0

• Started on natalizumab 300mg ivi monthly as part of a clinical trial

• NEDA (no evident disease activity) on natalizumab x 8 years

• Now wants to start a family; would you stop natalizumab?

• Natalizumab stopped

• Comes in 4 months later with a major spinal cord relapse

• MRI >50 Gd-enhancing lesions in the brain and a large Gd-enhancing lesions in the spinal cord with cord expansion

Considerations for Women of Childbearing Potential

Interferon β • In monkeys, increased rate of abortion. No malformations in

surviving animals

• Initiation of treatment is contraindicated during pregnancy

Glatiramer acetate

• Animal studies are insufficient with respect to effects on pregnancy;

embryonal/foetal development, parturition, and postnatal

development

• Contraindicated during pregnancy

Natalizumab

• Studies in guinea pigs and monkeys showed no evidence of

teratogenic effects or effects on growth of offspring

• Should not be used during pregnancy unless the clinical condition of

the woman requires treatment with natalizumab

Fingolimod

• Animal studies have shown reproductive toxicity, including foetal loss

and teratogenicity

• While on treatment, women should not become pregnant; if

pregnancy occurs, discontinuation of fingolimod is recommended

Animal studies, Clinical recommendations

Data from summary of product of characteristics (SmPC) for each therapy.

Considerations for Women of Child-bearing Potential

Teriflunomide

• Embryotoxic and teratogenic in rats and rabbits at doses in the

human therapeutic range

• Contraindicated in pregnancy

• Patient advised to contact physician if pregnancy is suspected;

institution of accelerated elimination may decrease risk to foetus

Alemtuzumab

• Dosing mice for 5 days during gestation resulted in significant

increases in dead or resorbed conceptuses and reduction in viable

foetuses

• Placental transfer and potential pharmacologic activity observed

• Contraception advised during treatment and for 4 months following

• Should be administered during pregnancy only if the potential benefit

justifies the potential risk to the foetus

• Thyroid disease poses special risks in women who are pregnant

(potential miscarriage, foetal effects such as mental retardation and

dwarfism, transient neonatal Graves’ disease)

Dimethyl fumarate • No malformations have been observed at any dose in rats or rabbits

• Should be used during pregnancy only if clearly needed and if the

potential benefit justifies the potential risk to the foetus

Animal studies, Clinical recommendations

Data from summary of product of characteristics (SmPC) for each therapy.

Conclusion

• DMT landscape is becoming increasingly complex – Changing role of clinical-nurse specialist and MSologist

• New tools are required to engage MSers in treatment decisions – Is not time some treatment algorithms?

• Treat-2-target of NEDA current paradigm – NEDA (zero-tolerance) vs. MEDA

– Expand to include end-organ damage metrics, e.g. BVL (NEDA-4)

• Most sequencing decisions are not evidence-based – scientific rationale

– registries and real-life data

– Head-2-head studies are needed

• Efficacy is not everything don’t forget safety , i.e. the risks and the benefits, tolerability, adherence, monitoring, pregnancy, etc…..

• Evidence-based stopping criteria

Rheumatoid arthritis End-stage joint disease

Questions

Sequencing of DMTs in Clinical Practice

Health & Medicine

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