Treatment Optimization in MS: When to Start, When to Shift, when to Stop

(1)

Treatment

Optimization in MS:

When to Start, When to

Shift, when to Stop

Mark S. Freedman

MSc MD FAAN FANA FRCPC

Director, Multiple Sclerosis Research Unit

University of Ottawa

Sr. Scientist, Ottawa Hospital Research Institute

Ottawa, Ontario CANADA

(2)

Disclosures

1. Receipt of research or educational grants:

BayerHealthcare; Genzyme

2. Receipt of honoraria or consultation fees:

BayerHealthcare, BiogenIdec, EMD Canada,

Genzyme, Novartis, Sanofi-Aventis, Teva Canada

Innovation

3. Member of a company advisory board, board

of directors or other similar

group:

BayerHealthcare, BiogenIdec, Hoffman

La-Roche, Merck Serono, Novartis, Opexa,

Sanofi-Aventis

,

4. Participation in a company sponsored

speaker‟s bureau:

(3)

MS: Pathological vs.

Clinical Course of Disease

Clinical Threshold

Axonal Loss

Demyelination

First Clinical Attack

Time Window for

Early Treatment

Inflammation

Dis e a s e par a m e te r

Relapsing – Remitting Transitional Secondary Progressive CIS

RIS

Treatment depends on

WHERE in the window you

think the patient is when

you are initiating treatment

Or old (silent) disease

presenting late?

Time (Years)

Are you dealing with new disease

presenting early?

New Diagnostic Criteria Have

Changed the Definition of CIS

0 2,000 4,000 6,000 8,000 10,000 12,000 Active Chronic active edge Chronic active core NAWM Control white 11,236 3,138 875 17 0.7

(4)

Early Treatment & Optimization

Maximizes Long-Term Benefit

Miller JR. J Manag Care Pharm. 2004;10(suppl S-b):S4-S11.

Time Symptom Onset Disabilit y Later treatment Earlier treatment Optimal Window of Opportunity

(5)

Goals of Therapy in MS Have Evolved

Along with Treatment Options

1983 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 IFNβ-1b 1993 _IM IFNβ-1a 1996 SC IFNβ-1a 1998 Natalizumab 2004/2006 GA 1997 Fingolimod 2010 Introduction of RRMS Therapies ? MSFC2 1995

Disease Activity Free3

2009

Sustained EDSS improvement4

2011

Establishment of Disability Outcome Measures

EDSS1

1983

Address

Symptoms Slow Disease Progression Stop Disease Progression

1. Kurtzke J. Neurology. 1983;33:1444-1452; 2. Whitaker J et al. Mult Scler. 1995;1:37-47; 3. Havrdová E et al. Lancet Neurol. 2009;8:254-260; 4. Phillips J et al. Mult Scler.

2011;17:970-979. Mitoxantrone 2000 BG12 Teriflunomide 2012 Repair Alemtuzumab 2013

(6)

Key Decision Points in the Treatment of

MS Are Also Evolving as Goals Change

Disease

progression

Initiating therapy

• When to start

• Choice of 1

st

_{- line therapy}

• Induction vs. escalation

Switching therapy

• Tolerability

• Safety

• Relapse/Progression/MRI

Stopping therapy

(7)

What are the factors

that should be

considered before

starting treatment?

Initiating

Treatment

(8)

What is the Time Course for Disease

Progression for the Patient?

DISEASE

PROGRESSION

Induction?

Escalation?

(9)

Prognostic Features in Early MS

Better prognosis Poorer prognosis

 Caucasian

 Monofocal onset

 Onset with optic neuritis or isolated sensory symptoms  Low relapse rate first 2–5 years  Long interval to second relapse  No or low disability at 5 years  Abnormal MRI

Low lesion load

 Afro-American or non-white  Multifocal onset

 Onset with motor, cerebellar, or bladder/bowel symptoms

 High relapse rate first 2–5 years  Short inter-attack latency

 Disability at 5 years  Abnormal MRI

≥2 contrast lesions ≥9 T₂ lesions

Miller DH, et al. J Manag Care Pharm 2004;10:S4–S11; Kantarci O, et al. Prognostic Factors in Multiple Sclerosis. In: Handbook of

(10)

Induction vs. Escalation Choice

Depends on Disease Perception

 The level of disease at any point in time will

dictate the need for an aggressive approach

– Consider the “window” position

 LOW risk: Escalation

– Perception is that patient is at a level of disease

where it is reasonable to start with agents

considered 1

st

_line

• Safety first

 HIGH risk: Induction

– Perception is that patient is already at an advancing

stage requiring rapid and definitive control

(11)

What is the “Risk” of a Patient for

Imminent Disease Progression?



What is the impression of the patient‟s

disease to date?

– Mild, early, typical

– Moderate or severe accumulated deficits,

later disease, more aggressive than normal

 How fast do we want a given treatment

to work?



What “other factors” (e.g. pregnancy,

adherence, moving) should be

(12)

Initiating Treatment :

“Early (Low Risk) Window”

 All agents are highly effective in the early

phase where all were tested

– IFN

b

, GA, teriflunomide, BG-12, fingolimod*

are considerations

 Safety important if no obvious difference

among agents

 Adherence important given that therapy will

be maintained for many years

 Early detection of sub-optimal response is

“key” as the “early” years are “prognostic”

(13)

Initiating Therapy:

“Late (High Risk) Window”

 Natalizumab or Fingolimod currently

considered for 2

nd

_{line use due to greater}

toxicity yet “perception” of greater efficacy

 Induction with Alemtuzumab

– Toxicity risk early or late, possibly prolonged

 Immunosuppression

– Mitoxantrone, cyclophosphamide

• Dose limitation due to accumulated toxicities

– Cladribine

– BMT

(14)

De-Escalating Therapy:

“Late (High Risk) Window”

Can induction therapy establish a long

lasting response that might be sustained

using a safer 1

st

line treatment?

– How much exposure time is needed for the

induction treatment?

• Most trials are only 2 years long

• May be dictated by risk of toxicity from prolonged

exposure (e.g. 2 years of Natalizumab)

– Will “rebound” be a problem?

(15)

Initiating Therapy:

“Sequence May Matter”

Will the choice of 1

st

_{therapy affect}

choices down the road?

– Will safety be an issue depending on the

choice of treatment?

• Can an immunosuppressant be followed safely by

natalizumab?

– Will response be an issue?

• If one starts with cladribine, could one follow with

(16)

Treatment Initiation (High Risk)

Induction

 Start with a 2

nd

_{or higher}

line agent

 Obtain a treatment

“response” for a given

period of time

 Revert back to a 1

st

_line

treatment to maintain

efficacy and minimize

toxicity or

 Maintain or escalate

further as necessary

Escalation

 Start with a 1

st

_{line agent}

– Monitor treatment

“response”

 If sub-optimal response,

move to a 2

nd

_{line agent}

– Monitor treatment

“response”

– Consider “de-escalation”

 If sub-optimal response,

move to another 2

nd

_line

or escalate to a 3

rd

_{line or}

higher agent

VS.

(17)

Defining “Response

to Treatment”

In the absence of a “cure”,

how do you define a

“suboptimal” response to

treatment?

(18)

Establish Monitoring Approach

 Approach needs to be reasonable & feasible

– Call-in instructions regarding tolerability or

indication of new attacks

– Clinic visits 3-4x/year for 1

st

_year

– Baseline & 1 year MRI with Gadolinium

• Baseline study should be performed when patient

is stable and enough time has elapsed to expect

that treatment is effective

 Pre-

conceived “plan B” for unacceptable

“breakthrough” disease or a deemed

“sub-optimal response to therapy”

(19)

What to Follow?

 Adherence

– is the drug tolerated?

– Managing side effects

– Laboratory monitoring

 Disease activity

– Relapse:

• Quality, quantity, recovery

– Progression

• EDSS, MSFC, cognition

(20)

Determining the level of concern to consider

treatment modification based on relapse outcomes

Low Medium High

Rate 1 attack in 2nd_{yr Tx 1 attack in 1}st_{yr Tx} _{> 1 attack in 1}st_{year of Tx}

Severity Mild

 No Steroids

 Min effect on ADL  1 FS involved  No motor/cerebellar involvement Moderate  Steroids required  Mod effect on ADL  >1 FS involved  Moderate motor/cerebellar involvement Severe  Steroids/hospital  Severe effect on ADL  >1 FS involved

 Severe

motor/cerebellar involvement

Recovery Prompt Incomplete at 3 mths Incomplete at 6 mths

Freedman MS, et al. Can J Neurol Sci 2013 FS, functional system; ADL, activities of daily living; mths, months

Note:

1. It is best to examine patients with more severe attacks 2. Recovery requires a re-examination at specific timepoints 3. Cognitive only attacks are hard to objectively define

(21)

Determining the level of concern to consider

treatment modification based on

progression outcomes

Baseline

EDSS Low Medium High

≤3.5 • <2 points • 2 points

confirmed at 3 mths

• >2 points confirmed at 6 mths • 2 points confirmed at 1 year

4–5 • <1 point • 1 point

confirmed at 6 mths

• >1 point confirmed at 6 mths • 1 point confirmed at 1 year

≥5.5 • 0.5 points confirmed at 6 mths • >0.5 points confirmed at 6 mths Clinically documented progression • No motor Minor sensory • Some motor, cerebellar or cognitive • Multiple domains affected • Pronounced motor, cerebellar, or cognitive

• Multiple domains affected

T25FW* • ≤ 20% confirmed 6 mths • > 20% and < 100% increase confirmed 6 mths • ≥ 100% increase confirmed 6 mths

Freedman MS, et al. Can J Neurol Sci 2013

(22)

Determining the level of concern to consider

treatment modification based on MRI outcomes

Change in MRI Categories Low Medium High Gd-enhancing lesions 1 lesion 2 lesions ≥ 3 lesions

New T2 lesions (per year)* 1 lesion 2 lesions ≥ 3 lesions

Freedman MS, et al. Can J Neurol Sci 2013 Note:

1. Routine follow-up MRI is recommended 6-12 months after initiating therapy (or in CIS if therapy is not initiated)

2. New T2 lesions that are also enhancing on the same scan are only counted once as unique active lesions

*There must be confidence that lesions are truly “new” compared to previous scans

Baseline study should be performed when patient is stable and enough time has elapsed to expect that treatment is effective

(23)

Each gauge represents a continuum from

0 no concern

The Canadian Treatment Optimization Model

Assessing concern whether to modify a treatment regimen

Freedman MS, et al. Can J Neurol Sci 2013

MRI

Progression

Relapse

Low concern Medium concern High concern

(24)

Each gauge represents a continuum from

0 no concern

The Canadian Treatment Optimization Model

Assessing concern whether to modify a treatment regimen

MRI

Progression

Relapse

Sub-optimal response

Consider treatment

change if:

Low concern Medium concern High concern

3 X low low low 2 X med med

1 X high

(25)

The Modified Rio Score

Identifying Poor Response to Therapy

 Patients are categorized by risk of progression based

on outcomes after 1 year of treatment

 Higher score predicts greater risk of progression in

2

nd

or later years if same treatment is maintained

Score

Criteria

0 ≤5 new T2 lesions and 0 relapses 1 ≤5 new T2 lesions and 1 relapse, or

>5 new T2 lesions and 0 relapses

2 ≤5 new T2 lesions and ≥2 relapses, or >5 new T2 lesions and 1 relapse

3 >5 new T2 lesions and ≥2 relapses

(26)

Disease

“Breakthrough” or

Sub-Optimal Response

to Treatment

How to define it, but

more importantly, how

to deal with it

(27)

Therapeutic Choices

 Landscape is changing rapidly but class of

agent is determined by the benefit : risk profile

 1

st

line agents (usually for “low” risk patients):

– proven efficacy - very low long-term risks

– IFN

b

, GA (long-term risks known)

– Teriflunomide, BG-12 (long-term risks unknown)

 2

nd

_{line agents:}

– Proven efficacy & known but possibly manageable

risks, however long-term risks known or unknown

– Natalizumab, Fingolimod

• Consider also the risk of discontinuation (i.e. rebound)

(28)

Managing Breakthrough Disease:

Lateral vs. Escalation Approach

 Lateral switch

– Perception is that patient is still at a low risk of

disease progression

– Another trial of a 1

st

_{line agent may be warranted}

 Escalation to higher line agent

– Temporary switch: (risk of progression medium)

• Period of exposure (e.g. 1-2 years) followed by a return

to a 1

st

_{line agent in order to minimize toxicity}

– Permanent switch: (risk of progression high)

• Disease level warrants a switch to ≥ 2

nd

_{line agent that}

(29)

Patient Experiencing a “Sub-optimal”

Treatment Response

1st_{line treatment} _{IFN, GA}_{(teriflunomide, BG12)} Perceived level

of disease

LOW HIGH

Switch Therapy Another 1st_line ₂nd_{line agent} Fingolimod, NZ