DMT Update MS Life Manchester 2014

DMT Update

Gavin Giovannoni

Barts and The London

The DMT pipeline

Interferons

Phase I

Phase II

Phase III

Marketed

Anti-proliferation agents

Avonex

Atacicept

Campath Rituximab

Novantrone

Rebif

Betaferon/ Extavia

Teriflunomide

Tysabri

Zenapax

Pixantrone

Targeted mAbs/Fc-Ab

Cladribine

Fingolimod

Azathioprine

= oral administration

= injectable

Riluzole

Symptomatic Tx

Vaccine, tolerisation

Tovaxin

ATL-1102

MM-093 BG12

AJM-300

Nerispirdine

Interferon Tau

Interferon omega

Peg IFNb (BIIB017)

Fc- IFb

ATX-MS-1467

Firategrast

Ofatumumab

Sativex

Lymphocyte trafficking

TBC4746

MLN-0002

Targeted Immune regulation

PI2301

R1295

Copaxone

Laquinimod

Fampridine SR

683699 (T-0047)

Ocrelizumab

LY-2127399

The ideal DMT

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

Treatment strategy

Treat early and effectively

Natural history

Delayed intervention

Later treatment

Treatment at diagnosis

Early intervention

Time Disease Onset

Dis

abili

ty

Time is brain

Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFN-1b trial

Goodin et al. Neurology 2012;78:1315-1322.

Regular Medical Care*

Primary Endpoint: All cause mortality free survival comparison between IFNβ-1b 250 µg eod vs. placebo per ITT

*Group approximately matched between DMTs

IFB-beta-1b approved

N=372

250 mcg

50 mcg

Placebo

1988 1993 2005 2006 2009 2010

98.4% ascertainment

Pivotal Trial

16-Year LTF 21-Year LTF

Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFN-1b trial

Goodin et al. Neurology 2012;78:1315-1322.

Consequences of increasing EDSS scores: loss of employment

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

MS patient’s QoL decreases tremendously dependent on the EDSS score

Mean utility

Utilities at early

disease

Utility at severe disease

Austria 0.55 0.90 0.05

Belgium 0.51 0.85 0.06

Germany 0.62 0.86 0.10

Italy 0.53 0.80 0.06

Netherlands 0.61 0.85 0.05

Spain 0.55 0.87 0.08

Sweden 0.546 0.825 0.047

Switzerland 0.59 0.89 0.1

UK 0.51 0.92 0.18

EQ-5D was used to calculate utilities: Utility is a measure of people's well-being or preferences for outcomes.

Mean utilities and EDSS in Germany 1= perfect health; 0 = worst health/dead

Source: based on G. Kobelt et al.: The European Journal of Health Economics, Volume 7; suppl. 2006

Treatment strategies

A

B

C

D

E

N M

Y X Moderate

Efficacy

Intermediate

Efficacy

High

Efficacy

1st-line

2nd-line

3rd-line

Survival Analysis

“Hit hard and early”

MS is an autoimmune

disease hypothesis

15–20 year

experiment

What is your treatment philosophy?

How bad is MS?

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

www.ms-res.org

Monitoring is important

Predictors of long-term outcome in MSers treated with interferon beta-1a

Bermel et al. Ann Neuol 2012.

Bermel et al. Ann Neuol 2012.

Predictors of long-term outcome in

MSers treated with interferon beta-1a

Treatment vs. Natural History

MS is an iceberg?

Clinical

MRI

Pathology

Treat-2-target

No evident disease activity (NEDA)

The relapsing MS DMT doughnut


Inactive RRMS

CIS

RIS or asymptomatic MS

Suboptimal responders ?

Active RRMS

Highly active RRMS


Inactive RRMS

CIS

RIS or asymptomatic MS

Suboptimal responders ?

Active RRMS IFNbeta / GA IFNbeta / GA

Highly active RRMS Fingolimod Natalizumab

Current UK practice

100 MSers

Who are the responders?

~20% responders

~40% sub-optimal responders

~40% non-responders

Question: Do you have active MS?

vs

1

2

3

Clinical

MRI

Biomarkers

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

The reality

Relapsing-remitting MS (RRMS)

Active disease?

Randomise

RES disease?

Y

N

N

Rx with Nz

Observation

Y

Current practice T2T-NEDA

Current 1st-line treatments IFNb, GA (Teri, BG12)

Current 1st-line treatments IFNb, GA (Teri, BG12)

6-monthly* clinical F-UP

Clinical responder?

Y

N

HAD or RES?

N

Y

Escalation/switch to upper tier natalizumab, fingolimod

(Alemz)

Switch in lower tier IFNb, GA

(Teri, BG12)

6-monthly* clinical/MRI F-UP

Clinical/MRI responder?

Y

N

Escalation/switch in upper tier natalizumab, fingolimod

(Alemz)

3-yr 1° outcome: confirmed disability progression 5-yr 1° outcome: time to confirmed EDSS 4.0

2° outcomes: MRI etc.

PROPOSED NEDA Rx Trial

NEDA = No Evident of Disease Activity T2T = treat-2-target

RES = rapidly evolving severe MS HAD = highly-active disease activity

* A clinical relapse between 6-monthly visits will trigger an unscheduled assessment for switching/escalation

GG, version 1.0 3rd Jan 2014

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.

DMT Summary

Efficacy

Ris

ks

+

+ -

-

GA

BMT

Mx

Alemz

aCD20

Lq BG12

Dac

Nz JCV+

Nz JCV-

IFNb Teri

Not licensed (but available in the NHS)

Licensed (available in the NHS)

Licensed (not available via NHS yet)

Late stage development (phase 3)

Fingo

KEY

DMT SUMMARY

What about pregnancy?

Questions MSers ask about pregnancy 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?

14. How 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 first start my family?

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-interferon beta antibodies affect my baby?

19. Can I have IVF? 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 contraceptive safer for my MS? Which contraceptive do you recommend?

What about vitamin D?

The effect of vitamin D-related interventions on multiple sclerosis relapses: a meta-analysis

James et al. Mult Scler. 2013 Oct;19(12):1571-9.

There is no evidence that vD supplements modify the course of MS. Low vD levels in MS can be due to reverse causation, i.e.

MS results in low vD levels.

Osteopaenia: z-scores are lower in MSers

Lumbar spine Femoral neck (NS)

Dobson et al. Mult Scler. 2012 Nov;18(11):1522-8.

The future?

Preventing end-organ damage

Control Multiple sclerosis

Brain atrophy occurs across all stages of the disease

De Stefano, et al. Neurology 2010

n= 963 MSers

Treatment Effect on Disability Strongly Predicted by Effect on T2 Lesion Volume and Brain Atrophy, Combined

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.

750

800

850

900

950

1000

1050

1100

1150

1200

1250

1300

1350

1400

1450

1500

30 35 40 45 50 55 60 65 70 75 80

Bra

in V

olu

me

(m

L)

Age (years)

Brain atrophy curves

Lower limit of normal

Average

Upper limit of normal

Hypothetical treatment effects

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1050

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Bra

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olu

me

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L)

Age (years)


MS lower limit

MS Average

MS Upper limit

-5%

-30%


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

-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

-5%

-30%

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1250

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1450

1500

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Bra

in V

olu

me

(m

L)

Age (years)


MS Average


-5%

-20%

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1250

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Bra

in V

olu

me

(m

L)

Age (years)


late treatment


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850

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950

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1050

1100

1150

1200

1250

1300

1350

1400

1450

1500

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Bra

in V

olu

me

(m

L)

Age (years)


-5%

-18%

early treatment

late treatment


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950

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1050

1100

1150

1200

1250

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1350

1400

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1500

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olu

me

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L)

Age (years)


-5% -11%

early very

highly-effective

treatment

late very

highly-effective

treatment

-15%


Conclusions 1. Current 1st-line or platform therapies are only moderately effective

a. Safe, but are associated with troublesome side effects and poor adherence

2. Escalation therapies (Fingolimod, Natalizumab & Mitoxantrone)

a. More effective but potential for more serious adverse effects

b. Tools and strategies have been developed to optimise risk:benefit; e.g natalizumab (PLEX & JCV

serology)

3. Emerging therapies

a. oral agents

i. Fingolimod – currently 2nd-line, may promote remyelination; if PPMS trial positive major

advantage over other emerging oral therapies (the halo effect)

ii. Teriflunomide – 1st-line therapy with a predictable SE profile based on the RA drug

leflunomide (the tortoise)

iii. BG12 or DMF – 1st-line, higher efficacy, interesting mode of action; ideal for combination

therapy (potential combi-tab)

iv. Laquinimod – not that effective as an anti-inflammatory, but has the neuroprotective

effects (the dark horse, ultimate combi-tab)

b. Alemtuzumab, 1st, 2nd or 3rd line; most potent of the DMTs but associated with risks

c. Daclizumab (biomarker) and anti-CD20 most exciting of the parenteral therapies in development

4. Patient factors ; risk assessment tools, education and a focus on wellness

5. Neuroprotection – several phase 2 trials currently been undertaken with oral agents

6. New target preventing end-organ damage

DMT Update MS Life Manchester 2014

Health & Medicine

Transcript of DMT Update MS Life Manchester 2014