Treatment algorithms in patients with ongoing disease activity

Gavin Giovannoni

Blizard Institute, Barts and The London School of Medicine and Dentistry

Disclosures

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-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals.

Regarding www.ms-res.org survey results in this presentation: please note that no personal identifiers were collected as part of these surveys and that by completing the surveys participants consented for their anonymous data to be analysed and presented by Professor Giovannoni.

Professor Giovannoni would like to acknowledge and thank Biogen-Idec, Genzyme and Novartis for making available data slides on natalizumab, alemtuzumab and fingolimod for this presentation.

Professor Giovannoni’s trip to Frankfurt has been kindly sponsored by Teva, therefore please interpret anything he says about Teva’s products in this context.

Risk of MS

Consequences of increasing EDSS scores: loss of employment1

0

10

20

30

40

50

60

70

80

90

Work Capacity by Disability Level

0.0/1.0 2.0 3.0 4.0 5.0 6.0 6.5 7.0 8.0/9.0

EDSS Score

Pro

po

rtio

n o

f M

Se

rs ≤

65

Ye

ars

Old

Wo

rkin

g (

%)

The proportion of MSers employed or on long-term sick leave is calculated as a percentage of MSers aged 65 or younger.

1. Kobelt G et al. J Neurol Neurosurg Psychiatry. 2006;77:918-926;

2. Pfleger CC et al. Mult Scler. 2010;16:121-126.

Spain

Sweden

Switzerland

United Kingdom

Netherlands

Italy

Germany

Belgium

Austria

~10 yrs2

Prognostic Factors

Number of Risk Factors Predicts Short-term Prognosis in Early MS

Risk Factors Evaluated (N=98)

1. Age at onset (<40 yrs vs >40 yrs)

2. Symptoms at onset (isolated sensory or cranial nerve vs motor or sensory plus motor)

3. MRI status before or at diagnosis (negative or suspicious vs suggestive)

4. Interval between the first and second attack (>2.5 yrs or <2.5 yrs)

5. Attack frequency in the first 2 yrs (≤2 vs >2)

6. Completeness of recovery from initial attacks (good vs poor)

Scott TF et al. Neurology 2000;55:689-93.

0

0.5

1

1.5

2

2.5

3

3.5

4

Low0 to 1

Risk Factors

Medium2 to 3

Risk Factors

High>3

Risk Factors

EDSS

Disability Accumulation by Risk Group

At MS diagnosis

Follow-up (mean 37 mos)

Brain Atrophy Rate (End Organ Damage) Correlated With Disease Course

• Brain atrophy accelerated in MSers with more advanced disease over 4 years of follow-up • Gray matter atrophy was significantly correlated with disability accumulation at 4 years

WMF=white matter fraction; GMF=gray matter fraction; BPF=brain parenchymal fraction

Fisher E et al. Ann Neurol 2008;64:255-65.

-0.45

-0.35

-0.25

-0.15

-0.05

0.05

0.15

Δ BPF Δ WMF Δ GMF

Control

CIS

CIS→MS

RRMS

RRMS→SPMS

SPMS

9

Treatment 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

Beyond NEDA (no evident disease activity)

Clinical activity

Focal MRI activity

Hidden focal and diffuse MRI activity

Microscopic or biochemical pathology

Biomarkers

*Odds of being in worst vs best quartile.

*EDSS>4.5. Bermel RA et al. Ann Neurol 2013;73: 95-103.

Ongoing Disease Activity During Interferon Treatment is Predictive of Long-Term Disability

Ongoing clinical or MRI disease activity during interferon treatment in a 2-year trial was

predictive of disability progression 15 years later

Activity During 2-Year Trial Odds of Severe Disability*

15 Years Later

>2 Gd lesions 8.96

>2 Relapses 4.44

>3 New T2 lesions 2.90

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

Treatment Strategy

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 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

The Traditional Approach to MS Treatment

• Heterogeneity of disease course across different MSers and over time can

affect treatment response1-3

• Depending on the definition used, up to 49% of MSers treated with a first-line

injectable therapy (IFNB) still have clinical disease activity1

1. Rio J et al. Ann Neurol 2006;59:344-52; 2. Miller A et al. J Neurol Sci 2008;274:68-75; 3. Rudick RA et al. Lancet Neurol 2009;8:545-59.

Figure adapted from Rio J et al. Curr Opin Neurol 2011; 24:230-7.

A

B

C

D

E

Y X

Moderate

efficacy

High efficacy or

very high efficacy

Initial

Treatment

IFNbeta

GA

Teri

DMF

Treatment Ladder

DMF

Fingo

Nz Az

Treating beyond symptoms with a view to improving IBDer outcomes in inflammatory bowel diseases

Sandborn et al. Journal of Crohn's and Colitis 2014(8):927–935

Moderate

Severe

TNF antagonist

± IMS

Steroids +IMS

Steroids

TNF antagonist

± IMS

Steroids +IMS

IMS + TNF antagonist

± IMS

Conventional step-care

Accelerated step-care

Early top-down

“FLIPPING THE PYRAMID”

Treatment Algorithm

23

Choose therapy

A B C

Define the individual’s MS

Treatment failure?

• MSer’s preferences? • Your choice?

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

e.g. NABs?

Monitoring

• MS prognosis based on clinical and MRI indices

• Life style and goals • Shared goals for therapy

Rebaseline

Rebaselining: • IFNβ, natalizumab, fingolimod,

teriflunomide, Dimethyl-Fumarate=3-6 months

• Glatiramer acetate=9 months • Alemtuzumab=24 months

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

• MSer’s preferences? • Your choice?

No Yes Yes

• Only one licensed induction therapy at present

Evolving Paradigm: Individualised Treatment Based on Projected Disease Course

Giovannoni et al. MSARD 2015 in press.

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

Sequencing of therapies

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

pati

en

ts, %

(9

5%

CI)

↑61.2% P<0.0001

CARE-MS II: NEDA by year

↑84.3% P<0.0001

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

Derisking Sequencing

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

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

Changing Treatment Target

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 MSers)

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

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

Beyond NEDA (no evident disease activity)

Clinical activity

Focal MRI activity

Hidden focal and diffuse MRI activity

Microscopic or biochemical pathology

Biomarkers

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?

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 – Has the time arrived for 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