All patients on an injectable should be switched to an oral

Bates (pro) vs. Giovannoni (against)

Professor Gavin Giovannoni

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

All patients on an injectable should be switched to an oral

Bates (pro) vs. Giovannoni (against)

Professor 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.

Why switch?

Why would you switch from an injectable?

1. Stable on treatment: no evident disease activity, no concerns

2. Stable on treatment: poor tolerance

3. Stable on treatment: poor adherence

4. Stable on treatment: want to fall pregnant

5. Breakthrough disease: suboptimal efficacy

No

Yes

Yes

Yes

Yes

But, why only an oral?

What is the aim of our treatments?

www.ms-res.org

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 P

ati

en

ts ≤

65

Ye

ars

Old

Wo

rkin

g (

%)

The proportion of patients employed or on long-term sick leave is calculated as a percentage of patients 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

Quality of life and disability

MS is one of the most common causes of neurological disability in young adults2

Natural history studies indicate that it takes a median time of 8, 20 and 30 years to reach the irreversible disability

levels of EDSS 4, 6 and 7, respectively3

Up to 75% increased annualized divorce rate4

Life expectancy is reduced by 5-10 years5

7.5x greater than suicide rate than the general population6

2 out of 3 patients with RRMS were unemployed due to the disease7

Utilit

y

EDSS Status

EDSS and utilitya show a significant inverse relationship1,b

aUtility measures are derived from EQ-5D using the EuroQoL instrument. bAdapted from Orme et al 2007. Error bars depict 95% confidence intervals. Half points on EDSS are not shown on graph axis, except at EDSS 6.5.

1.Orme M et al. Value In Health. 2007;10:54-60. 2.WHO. 2008.[TK] 3. Confavreaux, Compston. 2005.[TK] 4. Coles et al. 2001.[TK] 5. Confavreaux, Vukusic. 2006.[TK] 6. Sadovnick et al. Neurology 1991;41:1193-6.

7. Morales-Gonzales. Mult Scler. 2004;10:47-54.

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

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

Bermel et al. Ann Neuol 2012.

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. Neurology 2013.

Study or Subgroup Odds Ratio

IV, Random, 95% CI

Kinkel 2008

Prosperini 2009

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

Study or Subgroup Odds Ratio

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

Study or Subgroup Odds Ratio

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

Study or Subgroup Odds Ratio

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

Dobson et al. Neurology 2013.

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

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.

AAN 2013

AAN 2013

Reduced head and brain size for age and disproportionately smaller thalami in child-onset MS

Kerbrat Neurology. 2012 Jan 17;78(3):194-201.

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.

-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

Fingolimod has an early and sustained effect on the rate of brain atrophy compared with placebo and IFNb-1a IM

FREEDOMS, 2 years

Fingolimod 0.5 mg (n = 356)

Placebo (n = 329)

***

*

**

6 0 12 24

Time (months)

0

-0.4

-0.8

-1.2

-1.6

-2.0

−38%

vs placebo p<0.001

Ch

ange

in m

ean

BV

fro

m

bas

elin

e (%

)

TRANSFORMS, 1 year

0 12

Time (months)

0.0

-0.4

-0.6

-1.0

IFNb-1a IM (n = 359)

Fingolimod 0.5 mg (n = 368)

−40%

vs IFNb-1a IM p<0.001

*** -0.2

-0.8

Ch

ange

in m

ean

BV

fro

m

bas

elin

e (%

)

ITT population with evaluable MRI images. Note: n numbers for FREEDOMS data reflect the number of patients with available data at 24 months. *p<0.05; **p<0.01; ***p<0.001 vs comparator; p-values are for comparisons over Months 0-6, Months 0-12, Months 0-24 BV, brain volume; ITT, intent-to-treat. Gilenya™ Prescribing Information 19 April 2012. Reproduced with permission. Kappos L et al. N Engl J Med 2010; 362: 387-401, and Cohen JA et al. N Engl J Med 2010; 362: 402-415. Copyright © 2011 Massachusetts Medical Society. All rights reserved

Reduction in brain atrophy on alemtuzumab

Rheumatoid arthritis End-stage joint disease

IFNbeta

GA

Teri

DMF

Treatment Ladder

DMF Fingo

Nz Az

x

x

x x

IFNbeta

GA

Teri

DMF

Treatment Ladder

DMF Fingo

Nz Az

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

Why?

Adherence

• In MS, patients with long gaps in treatment are at greater risk of relapse than more adherent patients1

• Lower adherence to MS therapy is associated with a higher risk of relapse2

Treatment gaps and poor adherence are associated with increased relapse rates

Adherence is one of the keys to optimizing outcomes

1. Al-Sabbagh A et al. J Neurol 2008;255(Suppl. 2):S79 2. Steinberg SC et al. Clin Drug Invest 2010;30:89-100. Copyright © 2010, Adis Data Information BV MPR, Medication Possession Ratio

Comparison of relapse risk ratios by level of adherence in patients with MS2

80 <80 <75 <70 <65 <60 0.90

0.95

1.00

1.05

1.10

1.15

Rel

apse

ris

k ra

tio

MPR (%)

Forgetfulness is a primary cause of non-adherence

Pain at injection site

Not confident in treatment benefits

Other

Headache

Skin reaction

Depression

Financial reasons

Forgot to administer

Flu-like symptoms

Injection anxiety

Dosing schedule difficult/inconvenient

Weakness

Did not pick up medicine

Nobody available to administer

Pregnancy/planned pregnancy

Did not feel need for injection

Tired of taking injections

Fatigue

50%

20%

17%

15%

13%

12%

10%

10%

10%

9%

8%

6%

5%

4%

3%

2%

2%

1%

0 20 40 60 Patients (%)

Re

aso

ns

for

mis

sin

g o

ne

or

mo

re in

ject

ion

s

Psychological factors – forgetfulness and complacency

– impact adherence

Observational GAP study

Devonshire V et al. Eur J Neurol 2011;18:69-77 Patients could have reported more than one reason for non-adherence. When counting injection-related reasons for non-adherence, each patient was counted only once. GAP, Global Adherence Project

Do really think a tablet is going to improve poor adherence?

Alemtuzumab pharmacokinetics in MS

Clinical effects persist after Alemtuzumab is cleared from circulation

• Alemtuzumab serum concentrations low or undetectable within ~30 days after treatment

Alemtuzumab 12 mg administered at time 0 and 12 months.

Kovarova I, et al. Presented at: European Neurological Society; 2012; Prague; P341.

CARE-MS I: Mean Serum Concentration Over Time

Time on Study, mo

4,000

0

2,000

3,000

1,000

0 1 3 6 9 12 24 15 18 21

Co

nce

ntr

ation

(n

g/m

L)

13

Alemtuzumab

12 mg

Alemtuzumab 12 mg

Why?

Pregnancy

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 / registers indicate it is safe

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

CO-CZ-0056b

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

CO-CZ-0056b

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

Alemtuzumab pharmacokinetics in MS

Clinical effects persist after Alemtuzumab is cleared from circulation

• Alemtuzumab serum concentrations low or undetectable within ~30 days after treatment

Alemtuzumab 12 mg administered at time 0 and 12 months.

Kovarova I, et al. Presented at: European Neurological Society; 2012; Prague; P341.

CARE-MS I: Mean Serum Concentration Over Time

Time on Study, mo

4,000

0

2,000

3,000

1,000

0 1 3 6 9 12 24 15 18 21

Co

nce

ntr

ation

(n

g/m

L)

13

Alemtuzumab

12 mg

Alemtuzumab 12 mg

There is only one other drug has a better pregnancy profile than alemtuzumab and that was cladribine?

Conclusions

• MS is a bad disease • Mortality, disability, unemployment, divorce, suicide cognitive

impairment, etc.

• New treatment paradigm • Early effective treatment

• Therapeutic ladder; early treatment with rapid escalation

• Maintenance vs. induction therapy • Adherence and pregnancy major discriminators

• Improved risk mitigation tools

• Treat-2-target of NEDA

• Prevent end-organ damage (brain atrophy & CSF NF levels)

• Sustained improvement (treat early)

• Protect reserve capacity (healthy ageing)

• Long-term remission

• Is there any reason why you would limit yourself to an oral therapy?

Why would you switch from an injectable?

1. Stable on treatment: no evident disease activity, no concerns

2. Stable on treatment: poor tolerance

3. Stable on treatment: poor adherence

4. Stable on treatment: want to fall pregnant

5. Breakthrough disease: suboptimal efficacy

No

Yes

Yes

Yes

Yes

But, why only an oral? I urge you to vote NO!

Treatment Selection & treating-2-target

Choosing therapy

X Y Z

Define the Individual’s MS

No

Treatment failure? Yes

• Patient’s preferences?

• Your choice?

Individual measures:

• Evidence of disease activity?

• Tolerability/safety?

• Adherence?

• Drug or inhibitory markers?

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.

Gd

T2

CU

R

DP

15% vs 47% Δ 32%

13% vs 68% Δ 55%

6% vs 37% Δ 31%

Effect of natalizumab on clinical and radiological disease activity in MS: a retrospective analysis of the

Natalizumab Safety and Efficacy in Relapsing-Remitting MS (AFFIRM) study

Havrdova et al. Lancet Neurol. 2009 Mar;8(3):254-60.

Relapsing-MS

Active Inactive Highly-active Rapidly-evolving severe

What is active MS?

2001 Clinical

2009 Clinical and MRI

2014 Clinical or MRI

Active Inactive (NEDA or no evident disease activity) HA RES

What is your treatment aim?

2001 Clinical

2009 Clinical and MRI

2014 Clinical or MRI