defining suboptimal response to treatment in ms menactrims 2016

Defining suboptimal response to treatment in MS

Gavin Giovannoni

Barts and The London School of Medicine and Dentistry

London, UK

Disclosures

Professor Giovannoni has received personal compensation for participatingon Advisory Boards in relation to clinical trial design, trial steeringcommittees 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 VertexPharmaceuticals.

Professor Giovannoni would like to acknowledge several companies andcolleagues for making available data slides on for this presentation.

The changing treatment paradigm

IFNbeta

GA

Teri

DMFFingo

Nz

Az

Treatment Complexity

2014

7 IFNbeta

GA

Teri

DMF

FingoNz

Az

Dac

Anti-CD20

2016

9

100 MSers

Who are the responders?

?

40:60

?

80:20

What is active MS?

2001Clinical

2009Clinical and MRI

2014Clinical 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

Eligibility for treatment

2001Clinical


2014Clinical or MRI

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

No treatmentNatalizumab

(Tysabri)Fingolimod

(Gilenya)Treatment

Aim of treatment

2001Clinical


2014Clinical or MRI

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


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.

No evident disease activity: NEDA

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 What is NEDA?

× No relapses× No sustained disability progression (EDSS)× No MRI activity

× No new or enlarging T2 lesions× No Gd-enhancing lesions

DAF1,2

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

Rapid vs. Slow escalation

IFNbeta

GA

Teri

DMF

Treatment Ladder

DMF

Fingo

Nz Az

Early treatment with fingolimod improved time to confirmed relapse vs switching after 12 months

*Number of patients who completed the study during M36–48. #Interval non-completers are patients who did not continue to the next yearly time interval. For interval non-completers, M0–24 summarises the aggregate ARR from M0 to M24 for patients who discontinued during the interval of M12–24. M0–36 summarises the aggregate ARR from M0 to M36 for patients who discontinued during the interval of M24–36. M0–48 summarises the aggregate ARR from M0 to M48 for patients who discontinued during the interval of M36–48. Cohen JA et al. J Neurol Neurosurg Psychiatry 2015

Time to first confirmed relapse up to the end of study (core ITT population)

Fingolimod increased the proportion of patients achieving NEDA after switching from IFNβ-1a

Data presented are for the pooled fingolimod 0.5 and 1.25 mg groups. N, total number of patients in the group; n, number of patients achieving NEDA; IFN, interferon; NEDA, no evidence of disease activity (defined as no relapses, no 3-month disability progression and no MRI activity). Cohen JA et al. J Neurol NeurosurgPsychiatry 2015

Comparison of NEDA status in the core study and the first extension year by treatment group

IFN-switch group Continuous-fingolimod group

IFNβ-1a fingolimod

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 MRIActivity

Disease Activity Free

P<0.0001 P=0.0003 P<0.0001

51

36

51

21

83

6777

59

NoRelapses

P<0.0045

Over 24 months*

65.4

87.3

52.9

32.2

46.7

78.9

31.5

13.60

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=3.03P<0.0001

He et al. JAMA Neurol. 2015 Apr;72(4):405-13.

Comparison of switch to fingolimod or GA in active MS

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.

384650

67 64

0

20

40

60

80

100

Year 1 Year 2 Year 3

Pro

po

rtio

n o

f p

ati

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 p

ati

en

ts, %

(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 Teriflunomidein 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

dis

abili

ty p

rogr

essi

on

0.423 0.464 0.3030.463 0.536 0.3290.794 0.641 0.4720.0

0.2

0.4

0.6

0.8

1.0

>1 Prior DMT 1 Prior DMT No Prior DMT

0.072 0.201 0.1780.218 0.345 0.1760.298 0.299 0.2380.0

0.1

0.2

0.3

0.4

>1 Prior DMT 1 Prior DMT No Prior DMT

Teriflunomide 14 mgTeriflunomide 7 mgPlacebo

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

End-organ damage

Baseline Month 6

Month 12 Month 18

Baseline Month 6

Month 12 Month 18

Patient 1 Patient 2

End-organ damage

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.

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

• 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

Alemtuzumab Slows Brain Volume Loss Over 4-yrs Despite Most RRMS Patients Not Receiving Treatment for 3 Years

Coles et al. AAN 2015, P7.263

CARE-MS I CARE-MS II

Case study

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 NatalizumabJun-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?

Other discriminators

1. Safety (risk:benefit)

2. Tolerability

3. Adherence

4. Monitoring

5. Pregnancy

6. Regional / Cultural influences

7. Cost

8. Marketing

Treating to target in inflammatory bowel diseases

IMS, immunosuppressant; TNF, tumour necrosis factorReproduced from Gut, Ordás I, Feagan BG and Sandborn WJ, 1754–63, 2011 with permission from BMJ Publishing Group Ltd.

Conventionalstep care

TNFantagonist

± IMS

Corticosteroids+ IMS

Corticosteroids


Corticosteroids

TNFantagonist

± IMS

TNFantagonist

± IMS



TNFantagonist

± IMS


Corticosteroids


Acceleratedstep care

Moderate

Severe

IMS + TNFantagonist

Early top-down

Le

ve

l of

dis

ea

se

Flipping the pyramid

BARTS-MS T2T-NEDA ALGORITHM T2T = treating-to-target; NEDA = no evident disease activity

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,

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

• Patient’s preferences?• Your choice?

NoYes Yes

• Only one licensed induction therapy at present

IFNβ = interferon-beta; NABs = neutralizing antibodies; Rx = treatment

Adoption of innovations

Rapid adoption of innovations is “biggest unmet need of all”

Adapted from Everett M. Rogers, Diffusion of Innovations

Large disparities exist in access to disease-modifying therapies

1. Hollingworth S et al. J Clin Neurosci 2014;21:2083–7; 2. World Bank, 2015. http://data.worldbank.org/indicator/SP.POP.TOTL; 3. MSIF, 2013. http://www.atlasofms.org; 4. Wilsdon T et al. 2013. http://crai.com/sites/default/files/publications/CRA-Biogen-Access-to-MS-Treatment-Final-Report.pdf

Australia

Norway

Denmark

Sweden

Belgium

Austria

Germany

France

Finland

Spain

Italy

Slovenia

United Kingdom

Poland

0 20 40 60 80 100

Newer DMT

Established DMT

No DMT

All people with MS (%)

All data are from 2013

4

4

4

4

4

4

4

4

4

4

4

4

4

1–3

Established DMTsDMTs approved for relapsing forms of MS during the 1990s and reformulations or generic versions of these substances.

Newer DMTsDMTs approved for relapsing forms of MS that have a different mechanism of action from established DMTs.

1st line

2nd line

3rd line

www.msbrainhealth.org

Conclusion

• DMT landscape is becoming increasingly complex

– Changing role of nurse specialists and MSologist

• New tools are required to engage MSers in treatment decisions

– Is it time to develop 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

• Rapid adoption of innovations

• Holistic management of MS

– Brain Health, lifestyle issues, comorbidities, wellness, etc.

Questions

defining suboptimal response to treatment in ms menactrims 2016

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