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Peripheral & Central Nervous System Drugs Advisory Committee January 28, 2000. Mitoxantrone for Multiple Sclerosis (Novantrone ® ). Immunex Corporation. Mitoxantrone Approved Indications. Adult acute myeloid leukemia (1987) 12 mg/m 2 /day x 3 days every 4-6 weeks

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Peripheral central nervous system drugs advisory committee january 28 2000 l.jpg
Peripheral & Central Nervous System DrugsAdvisory Committee January 28, 2000

Mitoxantrone for Multiple Sclerosis

(Novantrone®)

Immunex Corporation


Mitoxantrone approved indications l.jpg
Mitoxantrone Approved Indications

  • Adult acute myeloid leukemia (1987)

    • 12 mg/m2/day x 3 days every 4-6 weeks

  • Symptomatic hormone-refractory prostate cancer (1996)

    • 12-14 mg/m2 every 3 weeks


Mitoxantrone use in cancer patients l.jpg
Mitoxantrone Use in Cancer Patients

  • Since approval

    • Over 180,000 patients treated in U.S.

    • Over 400,000 patients treated worldwide

  • Range of dose and schedule

    • 12 mg/m2/day x 3 days every 4-6 weeks

    • 8-14 mg/m2 repeated every 3-4 weeks

    • 30-80 mg/m2 single dose

  • Alone or in combination with other drugs

  • Well characterized safety profile


Mitoxantrone mechanism of action l.jpg

H H

NCH2CH2NCH2CH2OH

HO

O

2 HCL

O

HO

NCH2CH2NCH2CH2OH

H H

Mitoxantrone Mechanism of Action

  • Affects dividing and non-dividing cells via inhibition of DNA synthesis and repair

    • DNA intercalation

    • DNA topoisomerase II inhibition


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Proposed Mechanism of Action in MS

  • Antiproliferative effects -- reduces

    • B-lymphocytes

    • T-lymphocytes

    • Macrophages

  • Immunomodulatory effects

    • Decreases antigen presentation

    • Decreases cytokine production (IL-2, TNF, IFN)


Multiple sclerosis l.jpg
Multiple Sclerosis

  • MS is a debilitating disease

  • Afflicts 350,000+ Americans

  • 140,000+ with secondary progressive MS

    • No currently approved treatment options


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Mitoxantronefor MS - Regulatory History

  • End of Phase III meeting 11/2/98

  • Pre-NDA meeting 4/15/99

  • NDA submitted 6/4/99

  • Priority review status 7/26/99

  • Orphan designation granted 8/13/99


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Requested Approval

“To slow progression of neurological disability and reduce the relapse rate in patients with progressive forms of multiple sclerosis excluding primary progressive MS.”


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Presentation Agenda

  • IntroductionAnn Hayes, M.D. Senior Vice President Immunex Corporation

  • Efficacy & SafetyRichard Ghalie, M.D. Senior Director Immunex Corporation

  • Clinician’s Fred Lublin, M.D. Perspective Professor of Neurology MCP Hahnemann University


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Study Investigators

  • H. Peter Hartung, MD Chairman, Department of Neurology Graz University, Austria Chairman, Study 901

  • Gilles Edan, MD Chairman, Department of Neurology CHU Rennes, France Chairman, Study 902

  • Erich Mauch, MD Medical Director, Neurology Clinic Academic Hospital of Ulm University, Germany Chairman, Study 903


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Immunex Advisors

  • Hillel Panitch, MD Professor, Department of Neurology University of Maryland Baltimore, MD

  • Craig Smith, MD Clinical Professor of Neurology, Medicine and Ophthalmology University of Washington Seattle, WA

  • David Alberts, MD Professor of Medicine, Pharmacology and Public Health Associate Dean for Research University of Arizona Tucson, AZ


Mitoxantrone in multiple sclerosis ms l.jpg

Mitoxantrone in Multiple Sclerosis (MS)

Efficacy and Safety Review


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Mitoxantrone in Multiple SclerosisData Presentation and Discussion

  • Efficacy data from 2 randomized trials

  • Safety data

    • Two randomized trials (901-902)

    • One retrospective study (903)

    • 12+ years post marketing experience

  • Benefit and risk assessment

  • Discussion of questions raised by Dr. Katz


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Published Studies of Mitoxantrone in MS

No. of Dose (mg/m2) Author Patients Schedule

Gonsette (1990) 22 14 q 3 w

Kappos (1990) 14 10 q 3 w

Mauch (1992) 10 12 q 3 m

Noseworthy (1993) 13 8 q 3 w

Rugerro (1993) 14 8 q 3 w

Millefiorini (1997) 27 8 q m x 12 vs. placebo

Total 100 8-14 mg/m2 q 3w - 3m


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Studies in Mitoxantrone Filing in MS

Number of Patients

Study Design Mito Control Total

901 Phase III 127 64 191

902 Phase II 22 22 44

903 Retrospective 454 n/a 454

603 86 689


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Study 901Design and Efficacy Results


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Study 901 - MIMS Trial

  • Phase III, randomized, placebo-controlled study

  • 17 centers in 4 European countries

  • 194 patients

  • Chairs - Professors H-P. Hartung and R. Gonsette

  • Study approved by BfArM/Germany

  • June 1993 - July 1997

ECTRIMS - 1998, 1999 and AAN - 1999


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Study 901 - Inclusion Criteria

  • Age 18 to 55

  • MS according to Poser’s criteria

  • Secondary progressive or remittingprogressive* MS

  • EDSS progression  1 point in preceding18 months

  • Baseline EDSS from 3 to 6

* Relapsing remitting MS with residual deficit after relapse


Kurtzke edss scoring system l.jpg

10

7

6

5

3

0

Kurtzke EDSS Scoring System

Death from MS

Ambulation impaired

Wheelchair

Intermittent or unilateral assistance to walk 100 meters

Moderate disability in one FS or mild disability in 3-4 FS

Normal


Study 901 exclusion criteria l.jpg
Study 901 - Exclusion Criteria

  • Benign or primary progressive MS

  • Relapse or treatment with corticosteroids in preceding 8 weeks

  • Prior treatment with mitoxantrone

  • Immunosuppressive therapy in preceding9 months

  • Cardiac risk factors

  • Major medical illness


Study 901 design l.jpg
Study 901 - Design

Placebo

R

A

N

D

O

M

I

Z

E

Mitoxantrone 5 mg/m2

Mitoxantrone 12 mg/m2

  • Course every 3 months x 24 months

  • Follow-up at Month 36


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Study 901 - Masking Study Drug

  • Placebo (methylene blue) to mask patients

  • Evaluators of neurologic disability

    • Trained prior to study initiation

    • Masked to study drug

    • Not involved in patient management

  • MRI evaluators masked to study drug and outcomes

  • Treating physicians not masked to study drug

    • Drug administration and patient management

    • Evaluation of adverse events

    • Assessment and treatment of relapses


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Study 901 - Primary Efficacy Criterion

  • Single multivariate test* of 5 variables:

    • EDSS change from baseline

    • AI change from baseline

    • Number of relapses requiring treatment

    • Time to first treated relapse

    • SNS change from baseline

  • Mitoxantrone 12 mg/m2 vs placebo at  = 0.05

* Wei-Lachin procedure (1992)


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Study 901 - Test of Individual Efficacy Variables

  • If p  0.05 in multivariate test

  • Then test individual variables in pre-determined order

    • EDSS

    • Ambulation Index

    • No. of treated relapses

    • Time to 1st treated relapse

    • Standardized Neurologic Status score

  • At  = 0.05 for each endpoint

  • If p  0.05 for any variable, no further testing

  • 60 patients per group, power = 90%


Study 901 kurtzke expanded disability status scale edss l.jpg
Study 901 - Kurtzke Expanded Disability Status Scale (EDSS)

  • 10-point scale with 0.5 point increments

  • 7 functional systems (pyramidal, cerebellar, brain stem, sensorial, optic, bladder/bowel, mental) and other

  • EDSS  4.5 defined by functional scores

  • EDSS  5.0 defined by ambulation deficits


Study 901 ai and sns scales l.jpg
Study 901 - AI and SNS Scales

  • Ambulation Index (AI)

    • 10-point scale with 1-point increments

    • Evaluates ambulation deficits

    • AI  3 = help required for ambulation

  • Standardized Neurological Status (SNS) score

    • Developed and used in Germany  10 years

    • 99-point scale with 1-point increments

    • 5 functional systems (supraspinal, paresis, spasticity, sensorial, bladder)

    • Emphasizes supraspinal evaluation (50 points)


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Study 901 - Disposition of Patients

RandomizedN=194

Placebo

n=65

Mito 5

n=66

Mito 12

n=63

Withdrew after

1 course

n=1

Withdrew after

1 course

n=2

Not treated

n=1

Not treated

n=1

Not treated

n=1

n=64

n=64

n=60


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Study 901 - Early Drug Discontinuation

Number of Patients

Placebo Mito 5 Mito 12Reason for discontinuation (n=64) (n=64) (n=60)

Lack of efficacy 8 3 4

Patient refusal 6 3 2

Lost to follow-up 1 3 0

Adverse event 2 0 5

Other 0 1 1

Total discontinued 17 10 12

Completed 2 years 47 (73%) 54 (84%) 48 (80%)


Study 901 baseline demographics l.jpg

Placebo Mito 5 Mito 12 (n=64) (n=64) (n=60)

No. females (%) 31 (48) 39 (61) 28 (47)

Mean age (years) 40 40 40

Type of MS

Remittent progressive (%) 45 58 47

Secondary progressive (%) 55 42 53

Study 901 - Baseline Demographics


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Study 901 - Baseline DemographicsDisease Status

Placebo Mito 5 Mito 12Mean Values (n=64) (n=64) (n=60)

Duration of MS (years) 10 9 10

No. relapses prior year 1.3 1.4 1.3

 EDSS last 18 months 1.6 1.6 1.5

EDSS at entry 4.7 4.7 4.5


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Study 901 - Primary Efficacy Criterion

p-value

Placebo Mito 5 Mito 12 Mito 12

(n=64) (n=64) (n=60) vs Placebo

Multivariate primary efficacy criterion 0.0001

EDSS change (mean) 0.23 -0.23 -0.13 0.0194

AI change (mean) 0.77 0.41 0.30 0.0306

No. treated relapses (adj.) 76.8 46.9 24.1 0.0002

Time to 1st treatedrelapse (median, months) 14.2 NR NR 0.0004

SNS change (mean) 0.77 -0.38 -1.07 0.0269

NR = Median not reached within 24 months


Study 901 mean change in edss l.jpg
Study 901 - Mean Change in EDSS

0.3

0.2

0.23

0.1

p=0.0194†

Change M24  Baseline

0.0

-0.13

-0.1

-0.23

-0.2

-0.3

Placebo

Mito 5

Mito 12

† Mito 12 vs Placebo


Study 901 mean change in ai l.jpg
Study 901 - Mean Change in AI

0.8

0.77

0.7

0.6

0.5

0.4

Change M24  Baseline

p=0.0306†

0.41

0.3

0.30

0.2

0.1

0.0

Placebo

Mito 5

Mito 12

† Mito 12 vs Placebo


Study 901 mean change in sns score l.jpg

0.77

p=0.0269†

-0.38

-1.07

Placebo

Mito 5

Mito 12

Study 901 - Mean Change in SNS Score

1.0

0.5

0.0

Change M24  Baseline

-0.5

-1.0

-1.5

† Mito 12 vs Placebo


Study 901 total number treated relapses adjusted for dropouts l.jpg
Study 901 - Total Number Treated Relapses (Adjusted for Dropouts)

100

80

76.8

60

Adjusted No. of Relapses

69%

46.9

40

p=0.0002†

20

24.1

0

Placebo

Mito 5

Mito 12

† Mito 12 vs Placebo


Study 901 time to first treated relapse l.jpg
Study 901 - Time to First Treated Relapse Dropouts)

1.00

Placebo

Mito 5

0.75

Mito 12

p=0.0004

Mito 12 vs Placebo

Proportion Event-Free

0.50

0.25

0.00

0

3

6

9

12

15

18

21

24

Months


Study 901 secondary efficacy variables l.jpg

Patients (%) Dropouts)

p-value

Placebo Mito 5 Mito 12 Mito 12 (n=64) (n=64) (n=60) vs Placebo

EDSS 1.0 point increaseconfirmed 3 months later 22 14 8 0.036

EDSS 1.0 point increaseconfirmed 6 months later 19 9 7 0.045

Patients requiring a wheelchair 11 8 5 NS

Patients without relapses 36 39 57 0.021

Overall rating good/very good 17 42 43 0.001

QOL improvement 21 46 41 0.007

Worsening depression scale 40 44 37 NS

Hospitalization other than drug admin. 67 56 40 0.002

Study 901 - Secondary Efficacy Variables


Study 901 mean change in edss quarterly months 3 to 24 l.jpg

Placebo Dropouts)

Mito 12

-0.05

0.05

Mito 5

Study 901 - Mean Change in EDSS Quarterly Months 3 to 24

0.25

0.15

Change in EDSS

-0.15

-0.25

-0.35

3

6

9

12

15

18

21

24

Months


Study 901 edss 1 0 point deterioration sustained for 6 months l.jpg
Study 901 - EDSS Dropouts) 1.0 Point DeteriorationSustained for 6 Months

20

19%

(n=12)

15

64%

% (No.) of patients

10

p=0.045†

9%

(n=6)

7%

5

(n=4)

0

Placebo

Mito 5

Mito 12

† Mito 12 vs Placebo


Study 901 categorized 1 0 point edss change l.jpg
Study 901 - Categorized Dropouts) 1.0 PointEDSS Change

Number (%) of Patients

Placebo Mito 5 Mito 12

Change (n=64) (n=64) (n=60)

Worsened* 16 (25%) 10 (16%) 5 (8%)

Stable 41 (64%) 36 (56%) 43 (72%)

Improved 7 (11%) 18 (22%) 12 (20%)

* p=0.013 for Mito 12 vs Placebo


Study 901 patients without relapses l.jpg
Study 901 - Patients Without Relapses Dropouts)

p=0.021†

60

57%

50

(n=34)

40

39%

36%

% (No.) of patients

30

(n=25)

(n=23)

20

10

0

Placebo

Mito 5

Mito 12

† Mito 12 vs Placebo


Study 901 annualized relapse rate l.jpg
Study 901 - Annualized Relapse Rate Dropouts)

p-valueRelapse Placebo Mito 5 Mito 12 Mito 12Rate (n=43) (n=53) (n=42) vs placebo

Baseline 1.3 1.4 1.3 NS

Year 1 1.2 0.7 0.4 < 0.0001

Year 2 0.9 0.5 0.3 0.0001

Years 1 + 2 1.0 0.6 0.4 0.0002


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Study 901 - Neurologic Disability Assessment at Month 36* Dropouts)

3.5

Placebo (n=43)

3.28

3

Mito 5 (n=53)

2.5

Mito 12 (n=42)

2

Mean Change M36 - Baseline

1.5

1.51

1

1.13

0.5

0.61

0.55

0.19

0.46

0.04

0.10

0

AI

SNS

EDSS

* Not masked Months 24 to 36


Study 901 relapse rate months 24 to 36 l.jpg
Study 901 - Relapse Rate Months 24 to 36* Dropouts)

0.8

Placebo (n=43)

0.77

Mito 5 (n=52)

Mito 12 (n=42)

0.6

0.56

0.50

Mean Relapses Month 24 to 36

0.46

0.4

0.33

0.33

0.2

0

All Relapses

Treated Relapses

* Not masked Months 24 to 36


Study 901 time to first treated relapse month 0 to 36 l.jpg

Mito 5 Dropouts)

Mito 12

0

6

12

18

24

30

36

Study 901 - Time to First Treated Relapse - Month 0 to 36*

1.0

Placebo

0.8

0.6

Proportion Event-Free

0.4

Discontinuationof study drug

0.2

0.0

Months

* Not masked Months 24 to 36


Study 901 clinical efficacy conclusions l.jpg
Study 901 - Clinical Efficacy Conclusions Dropouts)

  • Mitoxantrone 12 mg/m2 vs placebo:

    • Slows neurologic disability

      • 1.0 point EDSS -- 64%

    • Decreases relapse rate

      • treated relapses -- 69%

  • No disease rebound 1 year after treatmentdiscontinuation

  • Dose response effect


Study 901 mri subgroup evaluation l.jpg
Study 901 - MRI Subgroup Evaluation Dropouts)

  • T1-w Gd-enhanced and T2-w scans

  • Scans performed at baseline, end of Years 1 and 2

  • 110 patients in specified sites

  • MRI review:

    • Centrally at the end of the study

    • Evaluators masked to study drug and clinical outcomes


Study 901 patients with gd enhancing lesions l.jpg
Study 901 - Patients with Dropouts)Gd-Enhancing Lesions

Placebo

p=0.105

at Month 24

Mito 12

40

29%

30

(n=10)

22%

19%

% (No.) of Patients

20

(n=8)

16%

15%

(n=7)

(n=5)

(n=5)

10

3%

(n=1)

0

0

12

24

0

12

24

Month


Study 901 patients with new gd enhancing lesions l.jpg
Study 901 - Patients with New Dropouts)Gd-Enhancing Lesions

Placebo

p=0.0236

at Month 24

Mito 12

19%

20

(n=7)

16%

15

(n=5)

12%

% (No.) of Patients

(n=4)

10

5

0%

(n=0)

0

12

24

12

24

Month


Study 901 change in total t2 weighted lesion load score 1 5 l.jpg
Study 901 - Change in Total T2-Weighted Lesion Load (Score 1 - 5)

Placebo

p=0.125

at Month 24

Mito 12

5

4.28

4

3

2.36

Mean Score Change

2

1

0.64

0.58

0

12

24

12

24

Month


Study 901 mri efficacy conclusions l.jpg
Study 901 - MRI Efficacy Conclusions - 5)

  • Mitoxantrone

    • Decreased Gd-enhancing lesions

    • Slowed progression of T2-w lesion load

  • Indicates a reduction of inflammation in CNS

  • Support clinical findings of study


Study 902 design and efficacy results l.jpg

Study 902 - 5)Design and Efficacy Results


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Study 902 - Phase II Trial in Active MS - 5)

  • Randomized, corticosteroid-controlled trial

  • 5 academic centers in France

  • 44 patients

  • Chair - Professor G. Edan

  • April 1992 - March 1995

Journal of Neurology, Neurosurgery and Psychiatry 1997


Study 902 inclusion criteria l.jpg
Study 902 - Inclusion Criteria - 5)

  • Age 18 to 45

  • Disease history of less than 10 years

  • Highly active disease

    • EDSS progression  2 points

    • Or  2 relapses

    • In preceding 12 months

  • Baseline EDSS  6.0


Study 902 exclusion criteria l.jpg
Study 902 - Exclusion Criteria - 5)

  • Corticosteroids in previous month

  • Immunosuppressive therapy in previous 3 months

  • Cardiac risk factors or major illness

  • Pregnancy or breast feeding


Study 902 design l.jpg
Study 902 - Design - 5)

Triage

Randomized Treatment

M 1

M 2

M 3

M 4

M 5

M 6

mitoxantrone 20 mg/month IV

+ methylprednisolone 1 g/month IV

M -2

M -1

M 0

M 1

M 2

M 3

M 4

M 5

M 6

methylprednisolone 1 g/month IV


Study 902 efficacy evaluations l.jpg
Study 902 - Efficacy Evaluations - 5)

  • Monthly MRI

    • MRI evaluators masked to study drug and outcome

  • Monthly clinical evaluations

    • Treating physicians not maskedto study drug

    • Evaluated EDSS, relapses, safety


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Study 902 - Study Endpoints - 5)

  • Primary MRI endpoint*

    • Number of patients with new Gd+ lesions monthly x 6

  • Secondary MRI endpoint

    • Number of new Gd+ lesions monthly x 6

  • Secondary clinical endpoints

    • EDSS

    • Relapse

  • Main comparisons at Month 6

* Miller et al, 1991


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Study 902 - Patient Disposition - 5)

Randomized

n=44

mP

n=22

Mito + mP

n=22

Withdrew

after 1 dose

n=1

Withdrew

after 1 dose

n=1

WithdrewLoE

n=5

mP completed study

n=16

Mito + mP completed study

n=21


Study 902 baseline demographics l.jpg
Study 902 - Baseline Demographics - 5)

mP Mito + mP (n=21) (n=21)

No. females (%) 11 (52) 15 (71)

Mean age (years) 32 31

Mean duration of MS (years) 5.7 6.9

No. RRMS/SPMS 15/6 17/4

Mean relapses in preceding 12 months 2.9 3.1

Mean EDSS 4.7 4.4

RRMS = Relapsing-remitting MS based on  2 relapses.

SPMS = Secondary progressive MS based on  2.0 points EDSS increase.


Study 902 patients with new gd enhancing lesions l.jpg

mP - 5)

Mito + mP

Study 902 - Patients With New Gd-Enhancing Lesions

* p=0.009

† p=0.030

‡ p=0.033

§ p=0.001

100

*

80

§

60

% of patients

40

86%

20

0

-1

0

1

2

3

4

5

6

Month


Study 902 mean sem number of new gd enhancing lesions l.jpg

mP - 5)

Mito + mP

Study 902 - Mean (±SEM) Number of New Gd-Enhancing Lesions

20

p=0.001at Month 6

15

Number of new Gd+ Lesions

10

5

0

-1

0

1

2

3

4

5

6

Month


Study 902 mean sem edss change l.jpg

mP - 5)

Mito + mP

Study 902 - Mean (±SEM) EDSS Change

2

p=0.013at Month 6

1

0

Mean EDSS Change

-1

-2

0

1

2

3

4

5

6

Month


Study 902 categorized 1 0 point edss change l.jpg
Study 902 - Categorized - 5) 1.0 Point EDSS Change

mP Mito + mP

Change (n=21) (n=21) p-value

Worsened 6 (29%) 1 (5%) 0.038

Stable 12 (57%) 8 (38%) 0.217

Improved 3 (14%) 12 (57%) 0.004


Study 902 relapse assessment l.jpg
Study 902 - Relapse Assessment - 5)

mP Mito + mP

(n=21) (n=21) p-value

Baseline annualized 2.9 3.1 NS

relapse rate

On study annualized 3.0 0.7 0.003 relapse rate

Patients free of 7 (33%) 14 (67%) 0.031 relapses on study


Study 902 efficacy conclusions l.jpg
Study 902 - Efficacy Conclusions - 5)

  • Mitoxantrone + mP vs mP alone

    • Decreases number of patients with newGd+ lesions (86%)

    • Slows progression of neurologic impairment (1.0 point EDSS -- 83%)

    • Decreases relapse rate (77%)



Mitoxantrone safety experience l.jpg

Study Description Patients - 5)

901 Phase III randomized, controlled 127

902 Phase II randomized, controlled 22

903 10 year retrospective study 454

Total 603

Mitoxantrone Safety Experience


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Study 901 - Discontinuation Due to AE - 5)

Group Month Reason for Withdrawal

Mito 12* 18 Nausea and emesis(n=5) 3 Depression 12  LVEF  10% from baseline 12 Urinary tract infection 18 Renal failure after retention

Mito 5 0 —

Placebo 15 Myocardial infarction (n=2) 18 Liver function abnormalities

* One additional patient withdrew after Cycle 1 due to MS progression, bilirubin = 3.3, and patient refusal.


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Study 901 - Clinical Adverse Events More Frequent (p - 5)0.05) in Either Mitoxantrone Group

% of Patients

Placebo Mito 5Mito 12 (n=64) (n=65) (n=62)

Nausea 20 55 76

Alopecia 31 38 61

UTI 13 29 32

Menstrual disorder 26 51 61

Amenorrhea 3 28 63

All AE were grade 1 or 2 except 5% of nausea in Mito 12.


Study 901 clinical adverse events in 10 of patients l.jpg
Study 901 - Clinical Adverse Events in - 5) 10% of Patients

% of Patients

Placebo Mito 5 Mito 12

Adverse Event (n=64) (n=65) (n=62)

Nausea 20 55 76

Alopecia 31 38 61

Urinary tract infection 13 29 32

Upper respiratory tract infection 52 51 53

Stomatitis 8 15 19

Arrhythmia 8 6 18

Diarrhea 11 25 16

Urine abnormal 6 5 11

ECG abnormal 3 5 11

Constipation 6 14 10

Rhinitis 14 11 8

Menstrual disorder 26 51 61

Amenorrhea 3 28 63


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Study 901 - Cardiac Monitoring - 5)

  • Clinical evaluation before each course

  • ECG before each course

  • Echocardiogram at baseline, Years 1, 2, 3


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Study 901 - Number of Patients with LVEF - 5) 50%

Number of Patients

Placebo Mito 5 Mito 12

Year 1 0/64 1/64 2/59

Year 2 1/47 1/54 1/52

Year 3 0/35 1/44 1/36

No congestive heart failure


Study 901 lvef values 50 month 24 to 36 l.jpg
Study 901 - LVEF - 5)Values  50%Month 24 to 36

Number of Patients

Mito 5 Mito 12

LVEF Change (n=43) (n=36)

Worsened from 1 1

 50% to  50%

Improved from 1 0

 50% to  50%

No congestive heart failure


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Study 901 - Additional Safety Information - 5)

  • No deaths

  • Pregnancy: 2 reported

    • 1 placebo - terminated pregnancy

    • 1 mitoxantrone 12 mg/m2 - normal child


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Study 901 - Hematology Results - 5) Normal*

Number of Patients

Placebo Mito 5Mito 12 (n=64) (n=64) (n=60)

Hemoglobin 14 15 14

Platelets 3 5 6

WBC 5 15 20

* Any grade, all reversible. No transfusions.

No difference in incidence of severe infections and hospitalizations for infection in the 3 groups.


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Study 901 - Serum Chemistries - 5) Normal*

Number of Patients

Placebo Mito 5 Mito 12 (n=64) (n=64) (n=60)

Creatinine 7 6 7

Bilirubin 15 13 10

GGT 20 19 19

SGOT 11 19 20

Alkaline phos. 8 8 5

* Any grade, all reversible.


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Study 902 - Adverse Events - 5)

  • Profile similar to Study 901

  • 3 adverse events considered severe (amenorrhea, depression/anorexia, contact lens intolerance)

  • No deaths on study

  • No cardiac toxicity (echocardiogram at baseline and M6)


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Study 902 - Grade 3-4 Hematologic Toxicity of Mito + mP* - 5)

% of Patients(n=21)

WBC  2,000/µL 48

ANC  1,000/µL 86

Hemoglobin  10 g/dL 0

Platelets  100,000/µL 0

* Nadir leukopenia Week 1 or 2


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Study 903 - Long Term Safety Database - 5)

  • Academic Clinic of Ulm University, Germany

  • Professor Erich Mauch

  • Retrospective analysis

  • Mitoxantrone given between 11/88 and 9/98

  • 454 patients

  • All patients included

ECTRIM - 1999


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Study 903 - Data Collection and - 5) Quality Assurance

  • Staff hired exclusively for data collection

  • Collection of specified safety andefficacy data

  • Attempt to obtain most recent follow-up

  • Information on treatment off site not collected

  • All CRFs reviewed by Dr. Mauch for accuracy


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Study 903 - Treatment Guidelines - 5)

  • Mitoxantrone 12 mg/m2 every 3 months

  • Dose adjustment or interval change as needed

  • Treatment discontinued if:

    • Not tolerated

    • Good disease response

    • Attempt to become pregnant


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Study 903 - Baseline Demographics - 5)

Parameter (454 patients)

Mean years since onset of MS 9.1

No. females (%) 276 (61%)

At start of mitoxantrone treatment:

Mean age (range) 37 (15-72)

Mean no. relapsesin preceding 12 months 1.02

Mean EDSS at baseline (range) 5.1 (1.0-9.5)

Mean EDSS deterioration in preceding 12 months 0.79

Mean follow-up in months (range) 47 (0-121)


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Study 903 - Mitoxantrone Dosing (N=454) - 5)

100

80

60

% (No.) of Patients

40%

40

32%

(n=181)

(n=144)

18%

20

11%

(n=80)

(n=49)

0

9

1-2

3-5

6-8

No. of Doses


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Study 903 - Mortality (N=454) - 5)

Number of Cause of Death Patients

Infections 9

Respiratory failure 5

Heart failure 2

Cachexia 1

Unknown - late deaths 3

Total 20 (4%)


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Study 903 - Pregnancies - 5)

  • Pregnancies

    • 4 during mitoxantrone treatment

    • 5 after discontinuing treatment

  • Births

    • 6 normal

    • 1 pregnant at data collection

    • 2 outcomes not available


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Study 903 - Cardiac Abnormalities - 5)

Cycle Mitoxantrone

of Cumulative Type of Event No. Event Dose (mg/m2)

Decreased LVEF 5 7-12 50-130

Arrhythmia 1 1 11

Mitral valve insuf. 1 4 41


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Mitoxantrone Cardiac Effects in - 5)Cancer Patients*

  • Mitoxantrone given every 3-4 weeks

  • Often with other chemotherapy/chest radiation

  • At cumulative dose of 140 mg/m2

    • Congestive heart failure = 2.6%

    • Moderate to severe  LVEF = 13%

  • Occur during or within a year of completing mitoxantrone therapy

* Published literature and Immunex databases


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Mitoxantrone Safety Conclusions - 5)

  • Adverse events mild or moderate

  • Manageable and reversible

  • Dose up to 100 mg/m2 in MS trials not associated with congestive heart failure

  • Myelosuppression

    • Reversible within 1 - 3 weeks

    • Not associated with severe infection

  • No secondary leukemia or myelodysplasia


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Risk & Benefit Assessment - 5)

  • Well characterized adverse events

    • Monitoring

    • Management

  • Clear benefit in progressive MS

  • Benefits outweigh risks

    • Disease stage without satisfactory therapy


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Acute Adverse Events - 5)

  • Mild to moderate intensity

  • Nausea and emesis: transient, manageable

  • Alopecia mild, reversible

  • Leukopenia

    • Grade 3-4 in  50% of patients

    • Between day 7-14

    • Reversible by day 21

    • Risk of neutropenic fever low


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Laboratory Monitoring - 5)

  • Serum chemistries (including LFT)

    • Before each course

  • Hemogram

    • Before each course

    • If fever develops at expectedleukocyte nadir


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Cardiac Monitoring - 5)

  • LVEF assessment

    • At baseline

    • At cumulative dose of 100 mg/m2

  • Assess risk/benefit and monitor LVEFbefore each course if:

    • Cumulative dose  100 mg/m2

    • LVEF decreases by  15% from baseline

  • Discontinue therapy if:

    • LVEF  50%

    • Cumulative dose  140 mg/m2


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Pregnancy - 5)

  • Mitoxantrone should not be used in pregnant women or in women attempting to become pregnant (already in label)


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Benefit of Mitoxantrone - Study 901 - 5)

  • Slows progression of neurologic impairment

    • Decreases 1.0 EDSS progression by 64%

  • Reduces relapses

    • Decreases treated relapses by 69%

  • Lessens CNS lesions

    • Substantial decrease in number of patients with Gd-enhanced lesions

    • Slows progression of T2w lesions


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Benefit of Mitoxantrone - - 5)Supportive Studies

  • Study 902 (mP vs Mitoxantrone + mP)

    • Slows progression of neurologic impairment (EDSS - 83%)

    • Decreases relapse rate (77%)

    • Decreases number of patients with newGd+ lesions (86%)

  • Study 903

    • Therapy feasible in practice setting



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Adequacy of Controlled Study 901 - 5)

  • Well designed, randomized, placebo-controlled

  • Prospectively defined entry criteria, endpoints, number of patients, and statistical analyses

  • Effect on disability and relapse using established scales

  • MRI prospectively limited to subset


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Adequacy of Controlled Study 902 - 5)

  • Well designed, randomized, controlled

  • Prospectively defined entry criteria, endpoints

  • Design typical of MRI-based trial

  • Effect on disability and relapse using established scales


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Mitoxantrone Slows Progression of Neurologic Disability - Study 901

  • Used 3 complementary disability scales

  • All 3 primary disability endpoints met

  • Secondary disability endpoints met

  • No rebound one year after stopping therapy


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Mitoxantrone Slows Progression of Neurologic Disability - Study 902

  • EDSS assessment unmasked

  • Results robust

    • Significant difference between mitoxantrone and control

    • Consistency of EDSS results in the2 randomized studies


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Mitoxantrone Decreases Relapse Study 902

  • Relapse definition/severity

    • prospectively defined in both studies

  • Consistency of results in the 2 studies

  • Highly significant vs control group

  • Consistency in all relapse evaluations


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MRI Results - Study 901 Study 902

  • MRI evaluations

    • In subset of patients

    • No stratification by baseline MRI

    • Study not sized for MRI endpoints

  • Decreased Gd+ lesions

    • Consistent with clinical results

    • Suggests biologic effect


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MRI Results - Study 902 Study 902

  • Design typical of MRI-based trial

  • Nine monthly scans per patient

  • MRI findings

    • Highly significant

    • Consistent with clinical results

    • Indicate mitoxantrone biologic effect

  • Consistent MRI results in both studies


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Dose - 12 mg/m Study 9022 Every 3 Months

  • Investigational dose in Study 901

  • Significantly better than placebo for all primary and most secondary variables

  • Dose of 20 mg (Study 902)  12 mg/m2

  • Substantial safety information in Study 901, 902, 903, and oncology safety databases


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Target Population Study 902

  • Patients with progressive forms of MS excluding primary progressive MS


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Mitoxantrone in Multiple Sclerosis: Study 902A Clinician’s Perspective

Fred D. Lublin, M.D.

Professor of NeurologyMCP Hahnemann University


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Progressive Study 902

relapsing

Clinical Courses of MS

Relapsing

remitting

Secondary progressive

Increasing Disability

Primary

progressive

Time


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Mechanisms of Worsening of MS Study 902

  • Relapsing-remitting disease with incomplete recovery (step-wise worsening)

  • Gradual, progressive worsening independent of relapses



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Secondary Study 902progressive

Progressive

relapsing

Clinical Courses of MS - Worsening Forms of Relapsing or Progressive Disease

Relapsing

remitting

Increasing Disability

Time


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Conclusions Study 902


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Effectiveness of Mitoxantrone in MS Study 902

  • Study 901

    • Primary endpoint - clinical

    • MRI data consistent with clinical findings

  • Study 902

    • Primary endpoint - MRI

    • Clinical data consistent with MRI findings


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Proposed Use of Mitoxantrone in MS Study 902

  • To slow progression of neurologic disability and reduce relapse rate

  • Patients with progressive forms of MS excluding primary progressive MS

  • Dose 12 mg/m2 every 3 months

  • Disease control for 2-3 years beneficial

  • Patients with limited therapeutic options


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