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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
Peripheral & Central Nervous System DrugsAdvisory Committee January 28, 2000

Mitoxantrone for Multiple Sclerosis

(Novantrone®)

Immunex Corporation

mitoxantrone approved indications
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
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
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
proposed mechanism of action in ms
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
Multiple Sclerosis
  • MS is a debilitating disease
  • Afflicts 350,000+ Americans
  • 140,000+ with secondary progressive MS
    • No currently approved treatment options
mitoxantrone for ms regulatory history
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
requested approval
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.”

presentation agenda
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
study investigators
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
immunex advisors
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

Mitoxantrone in Multiple Sclerosis (MS)

Efficacy and Safety Review

mitoxantrone in multiple sclerosis data presentation and discussion
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
published studies of mitoxantrone in ms
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

studies in mitoxantrone filing in ms
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

study 901 mims trial
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

study 901 inclusion criteria
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
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
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
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
study 901 masking study drug
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
study 901 primary efficacy criterion
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)

study 901 test of individual efficacy variables
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
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
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)
study 901 disposition of patients
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

study 901 early drug discontinuation
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
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
study 901 baseline demographics disease status
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

study 901 primary efficacy criterion31
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
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
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
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
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
Study 901 - Time to First Treated Relapse

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
Patients (%)

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
Placebo

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
Study 901 - EDSS  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
Study 901 - Categorized 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
Study 901 - Patients Without Relapses

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
Study 901 - Annualized Relapse Rate

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

study 901 neurologic disability assessment at month 36
Study 901 - Neurologic Disability Assessment at Month 36*

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
Study 901 - Relapse Rate Months 24 to 36*

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
Mito 5

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
Study 901 - Clinical Efficacy Conclusions
  • 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
Study 901 - MRI Subgroup Evaluation
  • 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
Study 901 - Patients with 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
Study 901 - Patients with New 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
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
Study 901 - MRI Efficacy Conclusions
  • 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 phase ii trial in active ms
Study 902 - Phase II Trial in Active MS
  • 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
Study 902 - Inclusion Criteria
  • 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
Study 902 - Exclusion Criteria
  • Corticosteroids in previous month
  • Immunosuppressive therapy in previous 3 months
  • Cardiac risk factors or major illness
  • Pregnancy or breast feeding
study 902 design
Study 902 - Design

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
Study 902 - Efficacy Evaluations
  • Monthly MRI
    • MRI evaluators masked to study drug and outcome
  • Monthly clinical evaluations
    • Treating physicians not maskedto study drug
    • Evaluated EDSS, relapses, safety
study 902 study endpoints
Study 902 - Study Endpoints
  • 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

study 902 patient disposition
Study 902 - Patient Disposition

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
Study 902 - Baseline Demographics

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
mP

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
mP

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
mP

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
Study 902 - Categorized  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
Study 902 - Relapse Assessment

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
Study 902 - Efficacy Conclusions
  • 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
Study Description Patients

901 Phase III randomized, controlled 127

902 Phase II randomized, controlled 22

903 10 year retrospective study 454

Total 603

Mitoxantrone Safety Experience
study 901 discontinuation due to ae
Study 901 - Discontinuation Due to AE

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.

study 901 clinical adverse events more frequent p 0 05 in either mitoxantrone group
Study 901 - Clinical Adverse Events More Frequent (p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
Study 901 - Clinical Adverse Events in 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

study 901 cardiac monitoring
Study 901 - Cardiac Monitoring
  • Clinical evaluation before each course
  • ECG before each course
  • Echocardiogram at baseline, Years 1, 2, 3
study 901 number of patients with lvef 50
Study 901 - Number of Patients with LVEF  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
Study 901 - LVEF 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

study 901 additional safety information
Study 901 - Additional Safety Information
  • No deaths
  • Pregnancy: 2 reported
    • 1 placebo - terminated pregnancy
    • 1 mitoxantrone 12 mg/m2 - normal child
study 901 hematology results normal
Study 901 - Hematology Results  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.

study 901 serum chemistries normal
Study 901 - Serum Chemistries  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.

study 902 adverse events
Study 902 - Adverse Events
  • 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)
study 902 grade 3 4 hematologic toxicity of mito mp
Study 902 - Grade 3-4 Hematologic Toxicity of Mito + mP*

% 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

study 903 long term safety database
Study 903 - Long Term Safety Database
  • 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

study 903 data collection and quality assurance
Study 903 - Data Collection and 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
study 903 treatment guidelines
Study 903 - Treatment Guidelines
  • 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
study 903 baseline demographics
Study 903 - Baseline Demographics

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)

study 903 mitoxantrone dosing n 454
Study 903 - Mitoxantrone Dosing (N=454)

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

study 903 mortality n 454
Study 903 - Mortality (N=454)

Number of Cause of Death Patients

Infections 9

Respiratory failure 5

Heart failure 2

Cachexia 1

Unknown - late deaths 3

Total 20 (4%)

study 903 pregnancies
Study 903 - Pregnancies
  • Pregnancies
    • 4 during mitoxantrone treatment
    • 5 after discontinuing treatment
  • Births
    • 6 normal
    • 1 pregnant at data collection
    • 2 outcomes not available
study 903 cardiac abnormalities
Study 903 - Cardiac Abnormalities

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

mitoxantrone cardiac effects in cancer patients
Mitoxantrone Cardiac Effects in 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

mitoxantrone safety conclusions
Mitoxantrone Safety Conclusions
  • 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
risk benefit assessment
Risk & Benefit Assessment
  • Well characterized adverse events
    • Monitoring
    • Management
  • Clear benefit in progressive MS
  • Benefits outweigh risks
    • Disease stage without satisfactory therapy
acute adverse events
Acute Adverse Events
  • 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
laboratory monitoring
Laboratory Monitoring
  • Serum chemistries (including LFT)
    • Before each course
  • Hemogram
    • Before each course
    • If fever develops at expectedleukocyte nadir
cardiac monitoring
Cardiac Monitoring
  • 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
pregnancy
Pregnancy
  • Mitoxantrone should not be used in pregnant women or in women attempting to become pregnant (already in label)
benefit of mitoxantrone study 901
Benefit of Mitoxantrone - Study 901
  • 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
benefit of mitoxantrone supportive studies
Benefit of Mitoxantrone - 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
adequacy of controlled study 901
Adequacy of Controlled Study 901
  • 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
adequacy of controlled study 902
Adequacy of Controlled Study 902
  • Well designed, randomized, controlled
  • Prospectively defined entry criteria, endpoints
  • Design typical of MRI-based trial
  • Effect on disability and relapse using established scales
mitoxantrone slows progression of neurologic disability study 901
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
mitoxantrone slows progression of neurologic disability study 902
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
mitoxantrone decreases relapse
Mitoxantrone Decreases Relapse
  • 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
mri results study 901
MRI Results - Study 901
  • 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
mri results study 902
MRI Results - 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
dose 12 mg m 2 every 3 months
Dose - 12 mg/m2 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
target population
Target Population
  • Patients with progressive forms of MS excluding primary progressive MS
mitoxantrone in multiple sclerosis a clinician s perspective

Mitoxantrone in Multiple Sclerosis:A Clinician’s Perspective

Fred D. Lublin, M.D.

Professor of NeurologyMCP Hahnemann University

clinical courses of ms
Progressive

relapsing

Clinical Courses of MS

Relapsing

remitting

Secondary progressive

Increasing Disability

Primary

progressive

Time

mechanisms of worsening of ms
Mechanisms of Worsening of MS
  • Relapsing-remitting disease with incomplete recovery (step-wise worsening)
  • Gradual, progressive worsening independent of relapses
clinical courses of ms worsening forms of relapsing or progressive disease
Secondary progressive

Progressive

relapsing

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

Relapsing

remitting

Increasing Disability

Time

effectiveness of mitoxantrone in ms
Effectiveness of Mitoxantrone in MS
  • Study 901
    • Primary endpoint - clinical
    • MRI data consistent with clinical findings
  • Study 902
    • Primary endpoint - MRI
    • Clinical data consistent with MRI findings
proposed use of mitoxantrone in ms
Proposed Use of Mitoxantrone in MS
  • 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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