Personalizing treatment choice

Personalizing Treatment Choice

International MS Physician Summit Prague, 22nd-23rd March 2014

Gavin Giovannoni

Barts and The London

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. I would like to acknowledge Mark Hughes, from Infusion, who helped me prepare some of my slides. Please note that Professor Giovannoni’s attendance at the 2014 MS Physician Summit, in Prague, was sponsored by Biogen-Idec.

http://www.ms-res.org/







Therapeutic Ideal

Reliable

long-term efficacy

Maintaining

QOL

Maintaining

independence

Maintaining the

ability to work

No issue for

pregnancy/fertility

Maximum reduction

of MS disease activity

Maximum

tolerability

Maximum

safety

Ease of use

Minor impact on

everyday life

QOL=quality of life.

Moving from Compliance to Concordance Requires a Culture Change

Concordance model Compliance model

Prescriber decides

diagnosis and treatment

Prescriber’s task is to

explain and instruct

Patient’s task is to

comprehend

Successful outcome is

compliance

Prescriber and patient negotiate

diagnosis and treatment

Prescriber elicits, explains,

persuades, and accommodates

Patient explains, considers, and

accommodates

Successful outcome is a

negotiated agreement

Royal Pharmaceutical Society of Great Britain. From compliance to concordance: achieving shared goals in medicine taking. London, 1997.

Canada: Deciding on an MS Treatment

Available from: mssociety.ca/en/pdf/EYO-ENG-web-2012.pdf. Accessed 13 March 2014.‎

Canada: Deciding on an MS Treatment

Available from: mssociety.ca/en/pdf/EYO-ENG-web-2012.pdf. Accessed 13 March 2014.‎

UK: Deciding on an MS Treatment

www.msdecisions.org.uk. Accessed 26 February 2014.

UK: Deciding on an MS Treatment

www.msdecisions.org.uk. Accessed 26 February 2014.

Compliance Model

“Trust me.

I am the

doctor”

Where are you on the diffusion curve?

Giovannoni G et al. Lancet Neurol. 2006;5:887-894.

http://www.campusi.com/bookFind/asp/bookFindPriceLoad.asp?prodId=0029266718

Patient FAQs Regarding the Impact of Therapy on Daily Life

• What is MS?

• Are you sure that I have MS?

• What type of MS do I have?

• What prognostic group do I fall into?

• What is the risk of not being treated with a DMT?

• Do I have active MS?

• Am I eligible for treatment with a DMT?

• Do you understand the difference between the treatment strategies of maintenance-and-escalation and induction therapy?

• Do you understand the concept of treat-2-target of no evident disease activity (NEDA)?

• What about pregnancy?

FAQ=frequently asked question; MS=multiple sclerosis; DMT= disease modifying therapy.

Question: What prognostic group do you fall into?

Good prognosis Poor prognosis

Young

Female sex

“Unifocal”‎onset

Isolated sensory symptom (optic

neuritis, sensory)

Full recovery from attack

Long interval to second relapse

No disability after 5 years

Normal MRI findings/low lesion load

No posterior fossa lesions

No brain atrophy

CSF negative for OCBs

Older age of onset

Male sex

“Multifocal“‎onset

Efferent system affected (motor, cerebellar,

bladder)

Partial or no recovery from a relapse

High relapse rate in the first 2 years

Disability after 5 years

Abnormal MRI findings with large lesion load

Posterior fossa lesions

Brain atrophy

CSF positive for OCBs

Genomic factors (eg, ApoE4)

MRI=magnetic resonance imaging; CSF=cerebrospinal fluid; OCB=oligoclonal bands; Apo=apolipoprotein.

Adapted from Miller D et al. Lancet Neurol. 2005:4;281-288.

0

10

20

30

40

50

60

70

80

0 5 10 15 20

Pa

tie

nts

Co

nve

rtin

g t

o EDSS‎≥3.0‎(%)

Years

0 Lesions

1–3 Lesions

4–10 Lesions

>10 Lesions

The data presented for years 5, 10, 14, and 20 were obtained from different publications based on the same longitudinal study.

The exact relationship between MRI findings and the clinical status of the patient is unknown. EDSS=Expanded Disability Status Scale.

Fisniku LK et al. Brain. 2008;131:808-817; Morrissey SP et al. Brain. 1993;116:135-146; O’Riordan JI et al. Brain. 1998;121:495-503;

Brex PA et al. N Engl J Med. 2002;346:158-164.

Baseline Number of Brain Lesions Predicts Progression to EDSS ≥3.0

Queen Square Study

Question: What prognostic group do you fall into?

Favourable

Indeterminate

Poor

time Aim of

treatment Giovannoni G. Barts & The London, UK, February 2014.

Question: What prognostic group do you fall into? Potential Consequences of the Disease

Question: Do You Have Active MS?

vs

1

2

3

Clinical

MRI

Biomarkers Giovannoni G. Barts & The London, UK, February 2014.

Treatment Selection

The individual MS patient: • MS prognosis • Life style and goals • Your goals for therapy

Individual MS patient’s measures: • Evidence of disease activity? • Tolerability/safety? • Adherence? • Drug or inhibitory markers?

Therapy: • Maintenance vs induction

• Moderate efficacy (1st-line) • Intermediate efficacy (2nd-line) • High-efficacy (3rd-line)

Monitoring: • Clinical

• Relapse • Disability progression • Risk profile for serious adverse events

• MRI • T2 & T1-Gd • Brain atrophy

• Biomarkers • NAbs • CSF neurofilament Gd=gadolinium; NAb=neutralising antibody.

Giovannoni G. Barts & The London, UK, February 2014.

Define the individual

MS‎patient’s‎disease

Treatment failure?

yes

no

Choose therapy

Monitoring

X Y Z

General Treatment Philosophy in 2008

Moderate

Efficacy

High

Efficacy

A

B

C

D

E


Increasing Choice: the Escalation Ladder

Moderate

Efficacy

Intermediate

Efficacy

High

Efficacy


A Conservative Alternative or, If Time=Brain, Is It Dangerous?

CO-CZ-0056b

N M

Y X Moderate

Efficacy

Intermediate

Efficacy

High

Efficacy

A

B

C

D

E


MS is an autoimmune

disease hypothesis

15−20 year

experiment

“T2T-NEDA & early‎”‎

Question: Do you understand the difference between the treatment strategies of maintenance, escalation and induction therapy?

What is your treatment philosophy? Maintenance-escalation vs induction

Survival

analysis

T2T=treat-to-target; NEDA=no evidence of disease activity.

Increasing Personalization: Matching Efficacy to Disease Activity

Moderate

Efficacy

Intermediate

Efficacy

High

Efficacy

Ongoing activity

but low concern

Ongoing activity

but high concern

Poor

(active disease)

Indeterminate

(active disease)

Favourable

(active disease)


An Aggressive Disease Requires a Strong Medicine

Moderate

Efficacy

Intermediate

Efficacy

High

Efficacy


Treat-to-Target: No Evidence of Disease Activity

Herd Immunity

Not immunised but

still healthy

Immunised and

healthy

Not immunised, sick

and contagious

http://en.wikipedia.org/wiki/Herd_immunity.

Accessed 7 March 2014.

A Hypothetical Population of Newly Diagnosed People with

CIS/MS

CIS=clinically isolated syndrome.

Hypothetical Long-term Outcomes Under the Current Treatment Paradigm


Hypothetical Long-term Outcomes Under the T2T-NEDA Paradigm


Question: What about pregnancy?

14. How do you treat hyperemesis gravidarum during pregnancy?

15. Should I continue taking my other drugs for my MS symptoms during

pregnancy?

16. What is the best treatment strategy for my MS? Should I go onto a DMT and

get my MS under control before starting a family or should I start my family

first?

17. What is the best treatment strategy for my MS to maximise my chances of

having a family and keeping my MS under control?

18. How will having neutralizing anti-IFN beta antibodies affect my baby?

19. Can I have in vitro fertilization? Will the drugs that are used to induce

ovulation affect my MS?

20. What dose of vitamin D do you advise during pregnancy?

21. Are oral contraceptives safer for my MS? Which contraceptive do you

recommend?

1. Does MS affect my fertility?

2. Will pregnancy affect the course of my MS?

3. Will I be able to breast feed after delivery?

4. How long before I fall pregnant must I stop my DMT?

5. If I fall pregnant on a DMT will this affect the baby?

6. Can I breast feed on my DMT?

7. Will I be able to be a good parent if I become disabled from my MS?

8. If I become disabled or unemployed as a result of MS will I be able to support

my children?

9. What is the risk of my children getting MS?

10. Can I do anything to prevent them from getting MS?

11. Am I more likely to need an assisted delivery because I have MS?

12. Will I be able to have a normal vaginal delivery?

13. Will I be able to have an epidural during labour?

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,‎transient‎neonatal‎Graves’‎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.

Key Takeaways

• There is a large gap between the therapeutic ideal and reality

• How are you going to close this gap?

• By practicing the concordance model?

• By being ready to answer your patients questions?

• We need to find balance between therapeutic objectives and patient needs (benefit-risk

assessment)

• What are your therapeutic objectives?

• Patient and physician perception of burden of therapy may differ

• Treatment philosophies vary widely

• Principal patient considerations impacting on treatment choice and adherence are

• Pregnancy

• Route of administration

• Dosing frequency

• Cognitive level

• Depression

• Belief in medicine/concept of disease (patient vs doctor)

• Understanding that effectiveness varies between individuals

Health & Medicine

Personalizing treatment choice