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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

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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

HH

NCH2CH2NCH2CH2OH

HO

O

2 HCL

O

HO

NCH2CH2NCH2CH2OH

HH

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 l.jpg

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


Mitoxantrone for ms regulatory history l.jpg

Mitoxantronefor MS - Regulatory History

  • End of Phase III meeting11/2/98

  • Pre-NDA meeting4/15/99

  • NDA submitted6/4/99

  • Priority review status7/26/99

  • Orphan designation granted8/13/99


Requested approval l.jpg

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 PresidentImmunex Corporation

  • Efficacy & SafetyRichard Ghalie, M.D. Senior DirectorImmunex Corporation

  • Clinician’s Fred Lublin, M.D. PerspectiveProfessor of NeurologyMCP Hahnemann University


Study investigators l.jpg

Study Investigators

  • H. Peter Hartung, MDChairman, Department of NeurologyGraz University, AustriaChairman, Study 901

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

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


Immunex advisors l.jpg

Immunex Advisors

  • Hillel Panitch, MDProfessor, Department of NeurologyUniversity of Maryland Baltimore, MD

  • Craig Smith, MDClinical Professor of Neurology,Medicine and Ophthalmology University of WashingtonSeattle, WA

  • David Alberts, MDProfessor of Medicine, Pharmacologyand Public HealthAssociate Dean for ResearchUniversity of ArizonaTucson, 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


Published studies of mitoxantrone in ms l.jpg

Published Studies of Mitoxantrone in MS

No. of Dose (mg/m2) AuthorPatients Schedule

Gonsette (1990) 2214 q 3 w

Kappos (1990) 1410 q 3 w

Mauch (1992) 1012 q 3 m

Noseworthy (1993) 13 8 q 3 w

Rugerro (1993) 14 8 q 3 w

Millefiorini (1997)278 q m x 12 vs. placebo

Total1008-14 mg/m2 q 3w - 3m


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Studies in Mitoxantrone Filing in MS

Number of Patients

StudyDesignMitoControlTotal

901Phase III12764191

902Phase II222244

903Retrospective454n/a454

60386689


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Study 901Design and Efficacy Results


Study 901 mims trial l.jpg

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 l.jpg

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


Study 901 masking study drug l.jpg

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 l.jpg

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


Study 901 early drug discontinuation l.jpg

Study 901 - Early Drug Discontinuation

Number of Patients

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

Lack of efficacy 834

Patient refusal632

Lost to follow-up130

Adverse event205

Other011

Total discontinued171012

Completed 2 years47 (73%)54 (84%)48 (80%)


Study 901 baseline demographics l.jpg

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

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

Mean age (years)404040

Type of MS

Remittent progressive (%)455847

Secondary progressive (%)554253

Study 901 - Baseline Demographics


Study 901 baseline demographics disease status l.jpg

Study 901 - Baseline DemographicsDisease Status

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

Duration of MS (years)10910

No. relapses prior year1.31.41.3

 EDSS last 18 months 1.61.61.5

EDSS at entry4.74.74.5


Study 901 primary efficacy criterion31 l.jpg

Study 901 - Primary Efficacy Criterion

p-value

Placebo Mito 5Mito 12Mito 12

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

Multivariate primary efficacy criterion0.0001

EDSS change (mean)0.23-0.23-0.130.0194

AI change (mean) 0.770.410.300.0306

No. treated relapses (adj.) 76.846.924.10.0002

Time to 1st treatedrelapse (median, months) 14.2NRNR0.0004

SNS change (mean) 0.77-0.38-1.070.0269

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

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 (%)

p-value

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

EDSS 1.0 point increaseconfirmed 3 months later221480.036

EDSS 1.0 point increaseconfirmed 6 months later19970.045

Patients requiring a wheelchair1185NS

Patients without relapses3639570.021

Overall rating good/very good1742430.001

QOL improvement2146410.007

Worsening depression scale404437NS

Hospitalization other than drug admin.6756400.002

Study 901 - Secondary Efficacy Variables


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

Placebo

Mito 12

-0.05

0.05

Mito 5

Study 901 - Mean Change in EDSSQuarterly 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


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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 l.jpg

Study 901 - Categorized 1.0 PointEDSS Change

Number (%) of Patients

PlaceboMito 5Mito 12

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

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

Stable41 (64%)36 (56%)43 (72%)

Improved7 (11%)18 (22%)12 (20%)

* p=0.013 for Mito 12 vs Placebo


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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 l.jpg

Study 901 - Annualized Relapse Rate

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

Baseline1.31.41.3NS

Year 11.20.70.4 < 0.0001

Year 20.90.50.3 0.0001

Years 1 + 2 1.00.60.4 0.0002


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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 l.jpg

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 l.jpg

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 l.jpg

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 l.jpg

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 l.jpg

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 l.jpg

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 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

  • 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 902Design and Efficacy Results


Study 902 phase ii trial in active ms l.jpg

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 l.jpg

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 l.jpg

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 l.jpg

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 l.jpg

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 l.jpg

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 l.jpg

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 l.jpg

Study 902 - Baseline Demographics

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

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

Mean age (years) 3231

Mean duration of MS (years) 5.76.9

No. RRMS/SPMS15/617/4

Mean relapses in preceding 12 months 2.93.1

Mean EDSS4.74.4

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

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

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

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  1.0 Point EDSS Change

mPMito + mP

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

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

Stable12 (57%)8 (38%)0.217

Improved3 (14%)12 (57%)0.004


Study 902 relapse assessment l.jpg

Study 902 - Relapse Assessment

mPMito + mP

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

Baseline annualized2.93.1NS

relapse rate

On study annualized 3.00.70.003 relapse rate

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


Study 902 efficacy conclusions l.jpg

Study 902 - Efficacy Conclusions

  • 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 data l.jpg

Mitoxantrone Safety Data


Mitoxantrone safety experience l.jpg

StudyDescriptionPatients

901Phase III randomized, controlled127

902Phase II randomized, controlled22

90310 year retrospective study454

Total603

Mitoxantrone Safety Experience


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Study 901 - Discontinuation Due to AE

GroupMonthReason for Withdrawal

Mito 12* 18Nausea and emesis(n=5)3Depression12 LVEF  10% from baseline12Urinary tract infection 18Renal failure after retention

Mito 5 0—

Placebo15Myocardial infarction (n=2)18Liver 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 l.jpg

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

% of Patients

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

Nausea205576

Alopecia313861

UTI132932

Menstrual disorder265161

Amenorrhea32863

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 10% of Patients

% of Patients

PlaceboMito 5Mito 12

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

Nausea205576

Alopecia313861

Urinary tract infection132932

Upper respiratory tract infection525153

Stomatitis81519

Arrhythmia8618

Diarrhea112516

Urine abnormal6511

ECG abnormal3511

Constipation61410

Rhinitis14118

Menstrual disorder265161

Amenorrhea32863


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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 l.jpg

Study 901 - Number of Patients with LVEF  50%

Number of Patients

PlaceboMito 5Mito 12

Year 10/641/642/59

Year 21/471/541/52

Year 30/351/441/36

No congestive heart failure


Study 901 lvef values 50 month 24 to 36 l.jpg

Study 901 - LVEF Values  50%Month 24 to 36

Number of Patients

Mito 5Mito 12

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

Worsened from 11

 50% to  50%

Improved from 10

 50% to  50%

No congestive heart failure


Study 901 additional safety information l.jpg

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 l.jpg

Study 901 - Hematology Results  Normal*

Number of Patients

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

Hemoglobin141514

Platelets356

WBC51520

* 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  Normal*

Number of Patients

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

Creatinine767

Bilirubin151310

GGT201919

SGOT111920

Alkaline phos.885

* Any grade, all reversible.


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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)


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

% of Patients(n=21)

WBC  2,000/µL48

ANC  1,000/µL 86

Hemoglobin  10 g/dL0

Platelets  100,000/µL0

* Nadir leukopenia Week 1 or 2


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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


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Study 903 - Data Collection andQuality 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

  • 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

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)

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)

Number of Cause of Death Patients

Infections9

Respiratory failure5

Heart failure 2

Cachexia1

Unknown - late deaths3

Total20 (4%)


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Study 903 - Pregnancies

  • 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

CycleMitoxantrone

of CumulativeType of EventNo.EventDose (mg/m2)

Decreased LVEF57-1250-130

Arrhythmia1111

Mitral valve insuf.1441


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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


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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


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Risk & Benefit Assessment

  • 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

  • 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

  • Serum chemistries (including LFT)

    • Before each course

  • Hemogram

    • Before each course

    • If fever develops at expectedleukocyte nadir


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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


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Pregnancy

  • 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

  • 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 - 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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Discussion


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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


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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


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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

  • 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

  • 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

  • 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/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


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Target Population

  • Patients with progressive forms of MS excluding primary progressive MS


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Mitoxantrone in Multiple Sclerosis:A Clinician’s Perspective

Fred D. Lublin, M.D.

Professor of NeurologyMCP Hahnemann University


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Progressive

relapsing

Clinical Courses of MS

Relapsing

remitting

Secondary progressive

Increasing Disability

Primary

progressive

Time


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Mechanisms of Worsening of MS

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

  • Gradual, progressive worsening independent of relapses


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Mechanisms of Worsening of MS


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Secondary progressive

Progressive

relapsing

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

Relapsing

remitting

Increasing Disability

Time


Conclusions l.jpg

Conclusions


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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


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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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