1

MS Patient CasesIran

May 2007Jack Burks, MD

Clinical Professor, NeurologistUniversity of Nevada School of Medicine

Reno, Nevada

Vice President/Chief Medical OfficerMultiple Sclerosis Association of America

PresidentMultiple Sclerosis Alliance

2

Important Issues in Treating MS: Illustrative Patient Cases

When to start therapy? How to decide on which therapy is the most

effective for a specific patient? How should patients be monitored to

determine good/poor Rx. responses? What is a poor response to treatment and

how should it be managed? How are side effects best managed? What is the future for current and emerging

therapies?

9

Patient 1:Deciding When to Initiate Treatment

10

Patient 1: Deciding When to Initiate Treatment

History 26-year-old secretary, mother of twins; no history of MS

or SLE Over 5-day period notices double vision, weakness in

the right arm and leg, unsteady gait, fatigue, and difficulty with memory when multitasking

Exam Diplopia on right gaze, mild right hemiparesis, and

wide-based, slightly ataxic gait Normal bedside mental status Husband stresses patient’s recent disorganization

11

Patient 1: Deciding When to Initiate Treatment

MRI 6 periventricular lesions, 1 pontine lesion, 1 high

cervical lesion on T2 MRI 4 GAD+ lesions

Lab work All negative Spinal tap not done

12

Neurologist’s Assessment

Patient had a CIS but does not meet the criteria for CDMS, could be ADEM

Steroids should be used in this patient, but a DMT is not appropriate at this stage

Is this the appropriate diagnosis? What goes into the decision process

to determine the appropriateness of utilizing a DMT?

13

Treat Early! Diagnosis of MSin Clinical Isolated Syndrome (CIS)

Lesions in Time and Space

Clinical Presentation Space Time(Add’l Requirements) (Add’l Requirements)

2 attacks; 2 locations No No

2 attacks; 1 location MRI abnormal or No2 MRI lesions + CSF

1 attack; 2 locations No MRI 3 months or

second attack

1 attack; 1 location (CIS) MRI abnormal or MRI 3 months 2 MRI lesions + CSF or second attack

Ref: McDonald, I. Annals of Neurology 2002

14

McDonald MRI Criteria for Dissemination in Time

First scan 3 months after clinical event New Gadolinium lesion

• Must not be the same site No new Gadolinium lesion:

• Repeat MRI at ≥3 months New T2 or gadolinium lesion

McDonald WI et al. Ann Neurol. 2001;50:121-127.The exact relationship between MRI findings and clinical status of patients is not completely understood.

15..

Example Application ofNew Diagnostic Criteria

3 months

T2

Gd

16

Polman Revision of McDonald Criteria (2005)

New T-2 MRI lesions at 1 month after CIS MRI (lesions in time)

Spinal cord lesions can be considered as a brain infratentorial and, if Gd-enhancing, can substitute for a brain Gd-enhancing lesion

Polman CH et al. Ann Neurol. 2005;58:840-846.

17

Patient 1: Follow-up After being treated with a course of IV

Solu-Medrol, the patient’s symptoms improved

At a 3-month follow-up visit: Clinical signs resolved Fatigue and memory problems less Neurology exam normal Previous GAD+ lesions had resolved 1 new GAD+ lesion and 2 new T2 lesions

18

Neurologist’s Assessment at Follow-up

Patient meets the McDonald criteria for CDMS/RRMS

The patient was started on treatment Do you agree with decision to treat? How do you decide which DMT to utilize in this

situation? Is there a difference or are they all the same? What do Evidence Based Medicine Analysis

and Class I Head to Head Trial indicate?

19

Patient was treated with IFNβ-1b

BENEFIT Trial

17 year follow-up data

AAN Treatment Guidelines

20Kappos L, Polman CH, Freedman MS, et al, for the BENEFIT Study Group. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology. 2006;67:1242-1249.

II. BENEFIT: Betaferon in CIS Objective:

To assess efficacy, safety, and tolerability of every-other-day (EOD) interferon beta-1b treatment in patients with a clinically isolated syndrome (CIS) suggestive of multiple sclerosis

Study design: Randomized, double-blind, placebo-controlled, parallel-group,

multicenter study with 468 patients Participants had experienced a first clinical demyelinating event, and

at least 2 clinically significant MRI-detected brain lesions Patients received Betaferon 250 µg or placebo SC EOD for 24 months

or until CDMS

Primary endpoints: Time to CDMS according to the modified Poser criteria Time to diagnosis of MS according to McDonald diagnostic criteria

21Kappos L, Polman CH, Freedman MS, et al, for the BENEFIT Study Group. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology. 2006;67:1242-1249.

Design of the BENEFIT study

22

28%

45%

Placebo

Betaferon

Risk reduction* of 50% over 2 years(Hazard ratio= 0.5)

*by adjusted proportional hazards regression

days

p<0.0001

Betaferon Reduced the Risk of CDMSby clinical criteria

Cli

nic

ally

Def

init

e M

S (

%)

23

28%

45%

Placebo

Betaferon

25%+ 363 days: + 142%

Day 255 Day 618

Betaferon Delayed the Onset of CDMS

Cli

nic

ally

Def

init

e M

S (

%)

days

24

Most Patients Develop MS by MRI Criteria Within 2 Years

McD

on

ald

M

S (

%)

days

MRI MRI MRI MRI MRI MRIMRI

Placebo

51%

85%

The BENEFIT Study Group

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Betaferon Doubles the Probability of Not Developing MS

Cumulative probability for patients not to develop MS according to McDonald Criteria over 2 years

15%

31%

0%

10%

20%

30%

40%

50%

Placebo Betaferon

Cum

ulat

ive

prob

abili

ty

Placebo (n= 176)

Betaferon (n= 292)

2 x

The BENEFIT Study Group

P<0.00001

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BENEFIT Trial: Early vs. Delayed Treatment: 3 year follow-up (2007)

Confirmed Progression (EDSS) Placebo then Betaferon 24% Betaferon from CIS 16% 40% decrease of confirmed progression with

early Betaferon treatment! (P=0.02)

No effect of NAbs on clinical outcomes

27The BENEFIT Study. Betaferon® in newly emerging multiple sclerosis for initial treatment: Clinical results [poster].

BENEFIT study: Discontinuation rates

Only 2.7% of Betaferon patients discontinued due to adverse events*

The majority of patients experienced no flu-like symptoms over 2 years

Factors for low rate of discontinuation include:

Dosage Titration

Analgesics: before injection

*From an analysis of patients who adhere to study protocol.

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Lessons from BENEFIT Trial Placebo patients studied in BENEFIT had a high risk

of progressing to MS according to the McDonald criteria 85% within 2 years, 51% after 6 months

In the BENEFIT study, every-other-day Betaferon significantly Reduced the risk of progression to CDMS (by 50%) Prolonged the time to CDMS by 1 year (+142%)

(based on the 25th percentiles) Delayed EDSS disability scores at 3 years

Every-other-day Betaferon is well tolerated and well accepted in patients

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17 year follow-up Rationale IFNB-1b was approved for the treatment of relapsing forms of

multiple sclerosis (MS) based on the results of a double-blind placebo-controlled study in which patients received placebo or IFNB-1b for 104 weeks and were followed up for up to 5 years

Results of this pivotal study showed IFNB-1b to be effective and well tolerated over this period

There are few data regarding the long-term benefit of IFNB treatment for more than 10 years. However, given that MS evolves over several decades, there is a need for longer-term data on treatment outcomes

This study assessed the long-term impact of IFNB-1b therapy in patients involved in the pivotal study

Ebers, George 2007

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Credibility factors in Betaferon 17 year follow-up data

Positive: Independent analysis Intent to treat analysis: treated vs. placebo

• About 90% case ascertainment • Betaferon effective and safe for 17 years

Concerns: Unknown treatment modalities for some patients

after trial ended High rate of mortality in placebo group after trial

ended. Is untreated MS a potentially fatal disease?

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*Versus patients on other DMTs or no treatment.

Goodin DS, Ebers G, Traboulsee A, et al, for the Betaferon® LTF Study group [poster]. American Neurological Association. October 8-11, 2006. Ebers G, Traboulsee A, Langdon D, Goodin D, Konieczny A, for the Betaferon®/Betaferon® LTF Study Group [poster]. American Academy of Neurology. April 1-8, 2006.

Long-term follow-up study: Betaferon significantly delayed disease progression over 17 years of treatment

Patients who continuously used Betaferon had nearly 60% more cane-free years from time of diagnosis*

Treatment with Betaferon delayed progression to SPMS by 6.6 years compared to other treatments or no treatment

After 17 years, the tolerability and safety profile of Betaferon remains excellent

32

Betaferon 17-Year LTF:Mortality Data by treatment group

Betaferon standard dose (n=124) 6%

Betaferon lower dose (n=125) 9%

Placebo (n=123) 19%

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Using Evidenced Based Medicine to Guide MS Therapy

AAN Guidelines

Cochrane Committee Reports

Head to Head Class I Trials

34Goodin DS, et al. Neurology. 2002;58:169-178.

Evidence-based Medicine: AAN Guidelines

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AAN Guidelines on DMT’s 1) Relapses and MRI

• All better than placebo (A)

2) Disability Progression• Interferons: Probably Effective (B)• Copaxone: Possibly Effective (C)

3) IFNs: Higher Dose / frequency more effective (B)

4) NAb: Conflicting data (U)• Utility of measuring is uncertain• Did not recommend testing requirements

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Patient 2: Evaluating the

Response to Disease Modifying Therapy

(DMT) in MS

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Patient 2: Evaluating Response to DMT

Current complaint 28-year-old surgical resident with RRMS Recently developed fatigue and frustration

but without impairment of surgical skills, even during extended operations

She is considering changing her MS therapy

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Patient 2: Evaluating Response to DMT (Cont.)

Past Neurological History 3.5 yrs ago: first symptom (unsteadiness of gait)

resolved without treatment or evaluation 3 years ago: bladder urgency, difficulty handwriting,

mild weakness in right leg• Brain MRI revealed 2 GAD+ lesions and 10 T2 lesions: locations

included periventricular areas, brain stem, cerebellum and corpus Callosum.

• CSF: + bands and IgG Synthesis: Other labs normal • Diagnosis of RRMS was made and treatment was I.V. Steroids

for 5 days. IFN B-1b was also begun. She recovered completely in one month

6 months later: mild blurred vision in left eye for two weeks with spontaneous recovery without steroids. No Evaluation

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Patient 2: Evaluating Response to DMT (Cont.)

Current evaluation: Neuro Exam Normal: Possible depression? MRI: No GAD lesions: T2 lesions are

smaller. No black holes or atrophy NAb test: + (1:100 titer)

40

Neurologists Assessment Since IFN B-1b, this patient has had only

one episode of (likely) mild optic neuritis – shortly after beginning therapy 3 yrs ago

Neuro exam was normal MRI demonstrated improvement since

beginning therapy Patient does not have enough evidence to

diagnose “suboptimal response” to current therapy.

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Neurologist’s Action Plan

Patient should remain on IFN B-1b Treat symptomatically for fatigue &

depression Patient and NAb status should be

reevaluated in 6 months

42

Questions

What is the utility of NAb testing in this clinically stable patient?

What will be the patient’s response to changing a treatment that is apparently working, especially if the change results in a treatment that may not work as well?

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Comments There remain differences of opinion regarding the

use NAb testing. 2007 AAN guidelines using EBM principles do not support routine NAb testing because

No class I EBM results on utility of NAb testing No standardized NAb test No established level of NAb relevance (?100-200) titer No EBM data on timing of NAb test No EBM data on clinical outcomes after changing therapy

based on + NAb test Recent data fails to correlate NAbs with poor

response to treatment.

44

Neutralizing Antibodies to Interferon B-1b are not

Associated with Disease Worsening in Multiple Sclerosis

Goodin DS., Hurwitz B., Noronha A. The Journal of International Medical Research, 2007; 35: 173-187

45

NAb Results:6698 Patients

Australia: All Patients on IFNβ-1b 37% NAb positive

North America: Suboptimal Responders 21.3 % NAb positive

Europe: Suboptimal Responders 27.6% NAb positive

Goodin, 2007

46

Conclusions:

Poor responders were less likely to have NAbs than responders

NAbs are not responsible for poor clinical responses and that NAb status is of little clinical value.

Goodin DS., Hurwitz B., Noronha A. The Journal of International Medical Research, 2007; 35: 173-187

47

Evaluating Response to DMT: Patient 2 Follow-up

6 months later she was NAb Θ on retest The patient has remained on IFN B-1b with no

new symptoms for the last 2 years Modafinil was added for fatigue: improvement SSRI taken for depression for one year. She is now a fully functioning surgeon

with no depression and minimal fatigue

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Patient 4: Managing Side Effects of DMT's

49

Patient 4: Managing Side Effects of DMT’s

34 yr old RRMS patient has been on IFN B-1b for 4 months

Neurologically stable but experiences flu like side effects and redness/pain at injection sites. She is unable to work because she feels “sick”, agitated, and depressed. Although feeling better in the past 2 months, she still wants to stop or switch treatment.

Initially she was started on the full dose of IFN B-1b without titration or analgesia pre-injection medication. Her husband has been injecting the drugs at an angle “to avoid going too deep”.

Liver function and CBC tests are normalMRI is unchanged

50

Neurologist’s Assessment

Since beginning therapy she has had no relapses or new MRI lesions

Side effects are caused by lack of dose titration when starting treatment and improper injection technique (Intradermal injections).

Depression could be from learning of her diagnosis of MS or worry about drug side effects vs. a direct effect from drug.

51

Neurologist’s Actions

Drug holiday for one month Re-start IFN B-1b at ¼ dose and titrate to ½,

then ¾ and then full dose each 2-3 weeks Close supervision and counseling Take analgesics before each shot Inject at 90 degrees Evaluate for depression on each visit, but no

anti depression medication at this time

52

Patient 4: Outcome

At 1 year patient tolerated treatment well with very few side effects and no recurrence of depression symptoms.

No missed days from work

53

Patient : Discussion

Drug side effects may mimic worsening of MS

Proper initiation of therapy prevents most early side effects

Aggressive side effect management can often avoid terminating therapy

54

Patient 5:Evaluating Possible Treatment Failures

55

Patient 5: Deciding When Treatment Is Not Working

A 43-year-old patient seeks a second opinion 5-year history MS Treated for 3 years with IFNβ-1a IM weekly Clinical exam

Weakness in extremities (worst in left lower) Uses cane for balance (4 months) Bilateral extensor plantar responses decreased vibration and position sensation in both legs and left hand Dysmetria bilaterally on finger to nose, and rapid alternating

movements bilaterally; dysmetria on heel to shin Mild memory dysfunction

56

Patient 5: Summary of Disease Course

A 43 yr old salesman is referred to you for a second opinion Case history

  2002 2003 2004 2005 2006Exacerbations 1 1 1 2 1

T2 lesions 12 ↑ ↑ ↑

GAD+ lesions 4 2 1 2 1

Brain atrophy No No No Yes Yes

Cognitive dysfunction

No No No No Yes

Progression No No No No Yes

IFNβ-1a IM No No Yes Yes Yes

NAb status ND ND Negative Negative Negative

57

Neurologist’s Assessment

The initial diagnosis of RRMS was correct The patient had 4 exacerbations during the

3 years on INF B-1a IM weekly The disease has transitioned from RRMS to

SPMS in the past 6 months Response to IFNB-1a has been suboptimal

in spite of negative NAb testing Therefore, treatment was switched to IFN

B-1b, 250 mcg god

58

Questions Raised by Patient 5

Was DMT started at the right time? What did his NAb test results mean? When did this patient’s disease become sub-

responsive to IFN B-1a IM? What criteria are most important for

determining when a patient has a suboptimal response to treatment?

When should natalizumab, and/or immunosuppressant drugs be considered?

59

Patient 5: Summary of Disease Course

A 43 yr old salesman is referred to you for a second opinion Case history

  2002 2003 2004 2005 2006Exacerbations 1 1 1 2 1

T2 lesions 12 ↑ ↑ ↑

GAD+ lesions 4 2 1 2 1

Brain atrophy No No No Yes Yes

Cognitive dysfunction

No No No No Yes

Progression No No No No Yes

IFNβ-1a IM No No Yes Yes Yes

NAb status ND ND Negative Negative Negative

60

Deciding When Treatment Is Not Working: Discussion

To provide optimal, care one must be prepared to change treatment if the course of the disease changes

Worsening neurological status (including cognition) with or without relapses are the most important criteria for deciding if a patient is progressing

61

Differential Diagnosis for Worsening Symptoms on DMT's

1. Poor compliance (common)

2. Side effects of DMT’s

3. Co-morbid conditions (hypothyroid, anemia, depression, infection)

4. Suboptimal Response (SORs) to DMT1. Diagnosis challenging (vs. natural treatment

history)

2. Under-diagnosed: (30%)

3. Treatment unclear: Lack of EBM data

62

Identifying SORs: Ongoing documentation is critical

Relapses Progression of Disability New MRI lesions (GAD lesions on T1) Increased MRI Burden of Disease (T2) Cognition? Often overlooked /undocumented New Imaging technologies? Not Yet

63

SOR: When to think about changing treatment?

1. Major relapse

2. 2 minor relapses in one year (Documented)

3. EDSS progression - not related to relapse

4. Decrease in cognitive function on testing

5. 1 new GAD lesion on MRI (Interferons)

6. 2 new T-2 lesions in MRI in one year

7. NAbs?

64

SOR: When to think “Why should I NOT Change treatment?”

1. 2 major relapses in one year2. Documented further EDSS progression on 2

exams 6 months apart3. Documented further decline of cognition on 2

exams 6 months apart. 4. 2 or more GAD lesions in 2 years (interferons)5. 3 or more new T-2 lesion in 2 years6. Considerable increase in brain atrophy,

permanent black holes

65

Management of SOR

Data is incomplete: Little EBM data:

“Therapeutic Window” is closing

Increase dose/frequency within class of drug

Change class of treatment

Add drug/combination therapy

66

Managing SOR on AvonexIncrease Dose

Double Dose weekly: Negative resultsIncrease frequency

Give every 2-4 days, IM: No data: ?PracticalSwitch to higher dosed, more frequent Interferon

Betaferon: INCOMIN Trial Data (MRI-Class I) Rebif: EVIDENCE Trial Data (Class I)

: EVIDENCE Trial Extension Data: Not Class I

Switch to or add Copaxone: No Data: Combination Trial underway: Appears safe

Add/switch to Mitoxantrone or other immuno-suppressants

Switch to Natalizumab

67

INdependent COMparison of INterferon (INCOMIN)

Trial Study Group

Durelli et al. Lancet 2002, 359:1453-60Durelli et al. Lancet 2002, 359:1453-60

A Multicenter Trial Comparing Clinical and

MRI Efficacy of Betaferon® and Avonex® in RRMS

68

Betaferon vs. AvonexThe INCOMIN Trial

Results: First 24 Months

Betaferon vs. AvonexThe INCOMIN Trial

Results: First 24 Months Avonex Betaferon

(n=92) (n=96) % p Avonex Betaferon

(n=92) (n=96) % p

T2 Lesion Free (0-24 mo) 19 (26%) 42 (55%) +53% 0.0003

% Change Lesion Load +11.7% -2.8% >100 0.0001

EDSS progression (0-24 mo) 28 (30%) 13 (14%) -46 0.005

New T2 lesions (6-12 mo) 33 (45%) 16 (21%) -52 0.002

Gd+ lesions (6-12 mo) 16 (22%) 7 (9%) -56 0.03

Gd Lesion Free (0-24 mo) 18 (25%) 39 (51%) +51 0.0008

Relapse-free (0-24 mo) 30 (33%) 46 (48%) +35 0.036

NAbs did not effect outcomes

69

The EVIDENCE Trial

Head-to-head, randomized, open label, evaluator-blinded comparison of Rebif (44 mcg tiw SC) with Avonex (30 mcg qw IM) in patients with RRMS

Neurology. 2002;59:1496-1506

EV idence of Interferon Dose-response:European North American Comparative

Efficacy Trial

EV idence of Interferon Dose-response:European North American Comparative

Efficacy Trial

Panitch H. Neurology 59: 1496-1503 (2004)

70

Summary Efficacy at Week 24 and Week 48

Week 24 Week 48

p-value Relative improvement

p-value Relative improvement

Odds ratio - relapsing 0.0005 47% 0.009 33%

Hazard ratio, time to relapse

0.001 37% 0.003

30%

Relapse rate 0.025 26% 0.093 16%

CU active

<0.001

48%

T2 lesions <0.001 50% <0.001 36%

T2 active scans <0.001 45% <0.001 38%

T2 inactive patients <0.001 39% <0.001 40%

Rebif vs Avonex

Rebif vs Avonex

Panitch H. Neurology 59: 1496-1503 (2004)

71

Avonex to Rebif Switch TrialAnnualized Relapse Rate

Final Comparative Phase vs Posttransition Phase

Panitch H. Neurology 59: 1496-1503 (2004)

Rebif 44 mcg tiw f 44 mcg tiw final comparative phase

Avonex 30 mcg qw final comparative phase

Rebif 44 mcg tiw posttransition 44 mcg tiw posttransitionfrom Rebif/Avonexfrom Rebif/Avonex

26%

0

0.2

0.4

0.6

0.8

An

nu

aliz

ed r

elap

se r

ate

(mea

n)

Avonex to Rebif (n=223)

P< 0.001

P=0.028

50%

Rebif to Rebif (n=272)

0.46

0.34

0.64

0.32

72

Managing SOR on Avonex Increase Dose

Double Dose weekly: Negative results Increase frequency

Give every 2-4 days, IM: No data: ?Practical Switch to higher dosed, more frequent Interferon

Betaferon: INCOMIN Trial Data Rebif: EVIDENCE Trial Data

: EVINDENCE Trial Extension Data Switch to Copaxone: No EBM data: Safe Add Copaxone: No Data: Combination Trial

underway: Appears safe Add/switch to Mitoxantrone or others Switch to Natalizumab

73

Managing SOR on Betaferon Increase Dose: Reasonable Pilot data: Well tolerated

OPTIMS Trial BEYOND Trial

Switch to Rebif: No data: Switch to Avonex:

No: INCOMIN Dose Reduction study Switch to Copaxone: Safe, No EBM data Add Copaxone: No data Add/Switch to Mitoxantrone or other

immunosuppression Switch to Natalizumab

74

INdependent COMparison of INterferon (INCOMIN)

Trial Study Group

Durelli et al. Lancet 2002, 359:1453-60Durelli et al. Lancet 2002, 359:1453-60

A Multicenter Trial Comparing Clinical and

MRI Efficacy of Betaferon® and Avonex® in RRMS

75

Dose-Reduction StudyBetaferon® to Avonex®

Switch TrialAvonex® Betaferon®

Exacerbation rate .09* .02*

% of patients with exacerbations 77%* 21%*

% of patients with sustained 23% (ns) 0% (ns) EDSS worsening

% of patients with MRI activity 85%* 36%*

* Statistically significant p<0.05

INCOMIN Trial Continuation

Barbero P. J. Neurol Sci. 15;222(1-2):13-9 (2004)

76

Managing SOR on Betaferon Increase Dose: Reasonable Pilot data: Well tolerated

OPTIMS Trial BEYOND Trial

Switch to Rebif: No data Switch to Avonex: No: INCOMIN Dose Reduction

study Switch to Copaxone: Safe, No EBM data Add Copaxone: No data Add/Switch to Mitoxantrone or other

immunosuppression Switch to Natalizumab

77

Managing SOR on Rebif

Increase Dose: No data: Not very practical Switch to Betaferon: No data: Maybe easier

to give even higher dose Switch to or add Copaxone : No data. Safe Add/Switch to Mitoxantrone or other

immunosuppression Switch to Natalizumab

78

Managing SOR on Copaxone

Increase dose? Double dose: positive PILOT data

Switch to Interferon: No EBM data: Most popular option: safe

Add Interferon: Combination Trial underway: safe

Add/switch to Mitoxantrone or others

79

Other SORs Treatment OptionsImmunosuppression:

Mitoxantrone (Novantrone) For worsening MS (RRMS and SPMS) Approved by FDA Popular for SOR treatment of ABCR drugs Relatively well tolerated Issues:

1. Occasional permanent amenorrhea

2. Cardiotoxicity: Dose dependent (2-3) years

3. Uncommon Risk of Leukemia (1 in 500?)

80

Other SOR Options

Pulses Methylprednisolone (I.V., monthly) Methotrexate (oral, weekly) Azathioprine (Imuran) (oral, daily) Cyclophosphamide (Cytoxan) Micophenolate (Cell Cept) IVIG Tysabri (Natalizumab): DO NOT ADD! Natalizumab (Tysabri) switch

81

Summary & Conclusions: SOR Diagnosis

SORs are common (30% or greater) but are under diagnosed

Is patient Compliant with drug? Regular documentation of MS course is

crucial: Relapses, MRI lesions, disability progression, ? Cognition

Rule out other causes of worsening MS : co-morbid conditions, pseudo exacerbations, depression, UTI, thyroid dysfunction

82

Summary & Conclusions: SOR Treatment

Little EBM data but therapeutic window closing: Options include:

1. Increase dose/frequency within class

2. Change class of treatment

3. Add different class of therapy (not natalizumab)

83

What is New?

Current and Emerging Therapies

84

A. Betaferon

1. BENEFIT Trial in CIS

2. 17 Year Follow up data

3. Betaferon vs. Double Dose Betaferon vs. Copaxone

85

B. Rebif

1. Reformulated Rebif

2. Rebif vs. Copaxone

3. Rebif in CIS

4. Cladribine Induction before Rebif

5. Rebif vs. Betaferon tolerability study

86

C. Copaxone

1. Copaxone in Primary Progressive MS: Discouraging

2. Double Dose Copaxone in RRMS: Encouraging

3. Copaxone in CIS (in progress)

4. Copaxone vs. Betaferon (in progress)

5. Copaxone vs. Rebif (data being analyzed)

87

D. Natalizumab (Tysabri)

1. Natalizumab vs. Placebo in RRMS

2. Natalizumab vs. Avonex

3. The PML issue

88

Oral Therapies

May improve convenience and compliance in MS therapy

Oral therapies now in phase 3 trials may be available in late 2010 Fingolimod (FTY720) Teriflunomide Cladribine Laquinimod

89

Monoclonal Antibodies (MAbs): Background

MAbs offer more favorable dosing regimens compared with current MS therapies (less frequent)

MAbs currently in use appear to be associated with specific side effects, eg, PML, Graves disease, ITP

Clinical trials of MAbs in MS are less advanced than those of oral therapies

Possible that no MAb currently in development will enter MS market before 2010

90

MAbs: Conclusions

Some striking efficacy results with MAbs in MS

Safety concerns must be allayed before MAbs are widely used in MS

91

Other Emerging Treatments

Fingolimod (oral) Campath (yearly) MBP82-98 (6 months) Rituximab (B-cell AB) (? PML) Cladribine (oral) Fumarate (BG-12) (oral) Teriflunomide (oral) Statins (oral): blocks IFNs Minocycline (oral Estriol (oral) Laguinimod (oral)

Fampridine-SR (Ambulation) NeuroVax (T-cell vaccine) Tovarin (anti T-cell) Bone Marrow Transplant IVIG Stem Cell Transplant Marijuana (symptomatic) Testosterone (Cognitive) Small Molecules CellCept (mycophenolate)

92

Other Treatment Approaches

Stem cells (bone marrow and embryonic)

Remyelinating agents

Neuroprotective agents

93

Patient 5A: Management of

Suboptimal Responders to both low and high

Dose Interferons

94

Patient 5A

39 year old male with very active RRMS for 3 years. He averages 2 attacks per year for all three years with only partial response to IV steroids. He was started on INFβ1-a I.M. (Avonex) weekly for the next two years. He was then switched to Rebif 44 TIW for the past year. He had 2 attacks during that last year with incomplete recovery with steroids.

95

Patient 5A

He is stable between attacks, but ongoing MRI activity is present. His exam reveals a bilateral intramuscular opthalmoplegia; right hemiparesis and ataxic gait requiring a cane to walk (EDSS=6).

96

Patient 5A What is your best treatment option

1. Keep on Rebif but double the dose2. Get an NAb test and stop Rebif if positive3. Switch to IFNβ-1b at double dose (500 ug)4. Add or Switch to Mitoxantrone5. Add or switch to Azathioprine6. Add or switch to cyclophosphide 7. IVIG8. Add Natalizumab (No!)9. Switch to Natalizumab10. Other options?

97

Patient 5B A 36 year old lady from Sari with

severe MS wants a child 36 year old, married11 years, MS started 9

years after Mother died in her arms Initial Symptoms 9 years ago: Fatigue,

legs weak, falling. After 3 months Neurologist diagnosed MS

by symptoms, exam and MRI with multiple lesions. She does remember an CSF.

Treated with IV steroids and improved

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Sari MS patient Relapse after 4 months, Treated with IV steroids and

improved back to “normal” Treated with Betaferon in 2000 and did well until 2004

when she stopped treatment to try “magic” therapy with alternative medicines, herbs and acupuncture.

Much worse symptoms until 2004 when saw a Neurologist and got Methetrexate followed by Betaferon. Her MS became more stable.

In 2006 stopped Betaferon to become pregnant. She had a miscarriage at 3 months and now wants to become Pregnant again. She fears her may leave her if she doesnot have a child.

3 weeks ago she became paraplegic with decreased feelings in both legs. She is considering Novantrone.

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36 year old Sari patient

Brief Exam reveals tearful lady with only slight movement in legs in a wheelchair

Spasticity in legs with sustained clonus at the ankles

Mild to moderate weakness in arms - L. more than R side

Ataxia and tremor - L more than R Marked decrease in position sense in legs Cranial nerves OK

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36 year old Sari patient

Meds include

Numerous vitamins

Baclofen

St John wort

Amantadine

MRI : 2003 Many T2 lesions

: 2005 More lesions with brain atrophy

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Issues for Sari patient

Early Treatment value Problems with Adherence to Betaferon Chemotherapy in lady who wants kids “Alternative” medicine versus Betaferon Pregnancy desires versus treatment desires Acute treatment and long term treatment options Rehab, Depression and family issues

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36 Year old Sari patient:My thoughts on Treatment

Must treat relapse immediately with IV steroids! If failure, try plasma phoresis or IVIG. Since she has done well on Betaferon in past, restart

with dose escalation ASAP – with IV steroids Treat with Betaferon for one year and re-evaluate. If sub

optimal response, try double dose of Betaferon if available data and positive by then. Or consider Novantrone or Tysabri. If she continues to do badly, consider Rituxamab in future – or other new med

Rehab, depression Rx and family counseling ASAP Consider adoption and not delay treatment for MS

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Patient 6:The Dilemma of

“Asymptomatic” MS

104

Patient 624 year old female with bitemporal throbbing “migraine” headaches associated with nausea, vomiting for 4 years associated with menstrual periods. Headaches last 2-6 hours and are helped with sumatriptan (Imitrex) if taken early in the course of the headache. She denies any fevers or chills. She is otherwise healthy with no family history of Neurological disease. No history of previous head injury.

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Patient 6

Her neurological exam was normal. MRI was done to rule out Meningioma, Aneurysm, or Arterial-venous malformation (AVM). Her T-2 weighted MRI revealed 6 white matter lesions ranging from 3-8mm, mainly periventricular. Radiologist conclusion “Multiple lesions, consistent with multiple sclerosis”.

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Patient 6

She comes to you for a second opinion:

1. Does she have MS? (or something else?)

2. Should she have an L.P., another MRI (GAD?), Evoked Potential testing, other workups?

3. Should she be treated with steroids or specific MS therapies

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Patient 6

What is your Differential Diagnosis?

How would you work up and treat this patient?

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Patient 6Differential Diagnosis

Collagen vascular disease (SLE)

CADASIL Thyroid disease Hypoglycemia Vitamin deficiencies Sjögren syndrome Behçet’s disease Myasthenia gravis Spino-cerebellar Degeneration

Adrenoleukodystrophies Lyme disease Syphilis TB & other CNS infections Sarcoidosis CNS malignancy CNS embolic disease AIDS PML

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Patient 6 Evaluation for MS:

Diagnosis and Progression Clinical history and exam best Ancillary tests

MRI CSF Evoked potentials Urological testing Cognitive tests EDSS, MSFC scale, Scripps scale

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Patient 6

Her evoked potential tests, ANA, Sed Rate, thyroid screen, VDRL, and other screening tests are normal. She has no GAD lesions or new T-2 lesions on repeat MRI done 2 weeks later. CSF is normal

111

Patient 6

Would you diagnose MS? Would you treat with Steroids? Would you treat with Interferons? Would you treat with both Steroids &

Interferons?

112

Patient 6

She was not given the diagnosis of MS and was not treated

113

Patient 6

If she had an identical twin with MS, would that change your opinion?

Identical twins have a 30% concordance rate for MS

114

Patient 6

One year later, she remained asymptomatic with a normal exam, but a repeat MRI showed 2 new T-2 lesions, but no GAD + lesions.

Does she now have MS?

Would you treat?

115

Patient 6

She was not diagnosed as MS and was not treated

116

Patient 6 One year later she had an episode of numbness on

left arm and leg along with fatigue and ataxia. Her MRI revealed 4 new T-2 lesions and 2 GAD + lesions

Would you diagnose MS? Would you treat with Steroids? Would you treat with Interferons? Would you treat with both Steroids & Interferons?

117

Patient 6 She was diagnosed as MS and treated with

steroids and Interferon β-1b with no further attacks in 5 years of follow-up.

Her MRI revealed no new T-2 or GAD lesions.

Would you stop her Interferon Treatment?

118

Patient 7: Differentiating MS,

Neuromyelitis Optica (DEVIC’s), and Asian

Optica-spinal MS

119

Patient 7

18 year old Asian male presented with decreased vision in right eye over 3 days with pain on eye movement: ophthalmologist diagnosed “optic neuritis” and treated with IV steroids with good results. Four months later he developed numbness and weakness in his legs with difficulty walking over a one week time period. His examination showed optic palor on right, decreased sensation below umbilicus and decreased strength in both legs.

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Patient 7

Babinski test was positive bilaterally, DTR’s were very active with transient clonus at At ankles. CSF tests were negative, except for 15 WBCs, MRI of spine showed a patchy longitudinal lesion from L1-4. Brain MRI showed 2 periventricular T-2 lesions. Extensive work up for other diseases was negative but acquaporin-4 antibody test was positive.

121

Patient 7

What is the most likely diagnosis?1. Classical MS

2. Asian MS (optic-spinal MS)

3. Neuro myelitis optica (NMO or Devics Disease)

4. CNS lymphoma or metastatic cancer

5. Other

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Neuromyelitis Optica Optic-Spinal MSRecurrent Optic

Neuritis Recurrent Myelitis

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Spectrum of MS:Neuromyelitis Optica (DEVIC's)

NMO Gender predilection: Female to Male ~10:1 Onset in all ages Ethnic predilection: No clear ethnic predilection

• May be present in all areas of the world at very low prevalence• In areas with high prevalence of MS, may be misdiagnosed as atypical

MS• In areas with low MS prevalence, differentiation from classic MS

becomes easier

Investigation Spinal cord–longitudinally extensive, central necrotic lesions Brain–some lesions now permitted CSF–pleocytosis (>50 white cells/μL), polymorphonuclear cells,

oligoclonal band negative NMO Antibody (Aquaporin 4) found in 70%

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Spectrum of MS:Optic-Spinal Multiple Sclerosis

OSMS (Asia) Gender predilection: Female to Male ~3:1 or more Ethnic predilection: Far-east Asian, Japanese, Latin

American

Investigation Brain–generally normal, but typical MS-like lesions

can be observed Spinal cord–multiple cord lesions of variable lengths CSF–Oligoclonal bands in about 30% of cases NMO Antibody found in >50% if long cord lesions (?NMO)

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Spectrum of MSRecurrent Optic Neuritis

If Brain and Spinal cord MRI normal

CDMS less likely BUT may convert to CDMS years later Treat with IV steroids, not DMT's

126

Spectrum of MSRecurrent Myelitis

If brain MRI normal, unlikely CDMS

If NMO Antibodies +, may be NMO

Treat with IV Steroids and Immunosuppressants

127

Patient 7

Patient was diagnosed as DEVIC’S (NMO)

He was treated with IV steroids only. He recovered considerable function but not completely.

128

Patient 7

Eight months later has another episode with decreased vision in left eye and numbness from his mid chest to his legs. Thoracic MRI revealed a new thoracic lesion covering 3 segments

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Patient 7 How would you treat him?

1. No treatment

2. IV Steroids

3. Interferon

4. Azathioprine

5. Mitoxantrone

6. Rituximab

7. Cyclophosphamide

8. IVIG

9. Natalizumab

10. Other drugs

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Patient 7

He was treated with IVMP and Aziathiaprine. He had 2 more attacks within the next 18 months, which left him blind in his left eye and he required a cane to walk. He was switched to IVIG and had another attack in 3 months. He was switched to Rituximab and has had no further attacks in 1 year of follow up