novantrone main presentation version 7.0 - 10/3/2015 m-1 mitoxantrone for multiple sclerosis...

Novantrone Main Presentation Version 7.0 - 04/19/23 M-1

Mitoxantrone for Mitoxantrone for Multiple SclerosisMultiple Sclerosis

(Novantrone(Novantrone®®))

Mitoxantrone for Mitoxantrone for Multiple SclerosisMultiple Sclerosis

(Novantrone(Novantrone®®))

Immunex CorporationImmunex Corporation Immunex CorporationImmunex Corporation

Peripheral & Central Nervous System Peripheral & Central Nervous System DrugsDrugsAdvisory CommitteeAdvisory Committee January 28, January 28, 20002000


Mitoxantrone Approved Mitoxantrone Approved IndicationsIndications

• Adult acute myeloid leukemia (1987)Adult acute myeloid leukemia (1987)

– 12 mg/m12 mg/m22/day x 3 days every 4-6 /day x 3 days every 4-6 weeksweeks

• Symptomatic hormone-refractory Symptomatic hormone-refractory prostate cancer (1996)prostate cancer (1996)

– 12-14 mg/m12-14 mg/m22 every 3 weeks every 3 weeks


Mitoxantrone Use in Cancer Mitoxantrone Use in Cancer PatientsPatients

• Since approvalSince approval– Over 180,000 patients treated in U.S. Over 180,000 patients treated in U.S. – Over 400,000 patients treated Over 400,000 patients treated

worldwideworldwide

• Range of dose and scheduleRange of dose and schedule– 12 mg/m12 mg/m22/day x 3 days every 4-6 /day x 3 days every 4-6

weeksweeks– 8-14 mg/m8-14 mg/m22 repeated every 3-4 repeated every 3-4

weeksweeks– 30-80 mg/m30-80 mg/m22 single dose single dose

• Alone or in combination with other Alone or in combination with other drugsdrugs

• Well characterized safety profileWell characterized safety profile


Mitoxantrone Mechanism of Mitoxantrone Mechanism of ActionAction

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

– DNA intercalationDNA intercalation

– DNA topoisomerase II inhibitionDNA topoisomerase II inhibition

HOHO OO

HOHO OO

2 HCL2 HCL

NCHNCH22CHCH22NCHNCH22CHCH22OHOHHH HH

HH HHNCHNCH22CHCH22NCHNCH22CHCH22OHOH


Proposed Mechanism of Action Proposed Mechanism of Action in MSin MS

• Antiproliferative effects -- reducesAntiproliferative effects -- reduces

– B-lymphocytesB-lymphocytes

– T-lymphocytesT-lymphocytes

– MacrophagesMacrophages

• Immunomodulatory effectsImmunomodulatory effects

– Decreases antigen presentationDecreases antigen presentation

– Decreases cytokine production Decreases cytokine production (IL-2, TNF(IL-2, TNF, IFN, IFN))


Multiple SclerosisMultiple Sclerosis

• MS is a debilitating diseaseMS is a debilitating disease

• Afflicts 350,000+ AmericansAfflicts 350,000+ Americans

• 140,000+ with secondary progressive 140,000+ with secondary progressive MSMS

– No currently approved treatment No currently approved treatment optionsoptions


MitoxantroneMitoxantrone for MS - for MS - Regulatory HistoryRegulatory History

• End of Phase III meetingEnd of Phase III meeting 11/2/9811/2/98

• Pre-NDA meetingPre-NDA meeting 4/15/994/15/99

• NDA submittedNDA submitted 6/4/996/4/99

• Priority review statusPriority review status 7/26/997/26/99

• Orphan designation grantedOrphan designation granted 8/13/998/13/99


Requested ApprovalRequested Approval

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


Presentation AgendaPresentation Agenda

• IntroductionIntroduction Ann Hayes, M.D.Ann Hayes, M.D.Senior Vice PresidentSenior Vice PresidentImmunex CorporationImmunex Corporation

•Efficacy & SafetyEfficacy & Safety Richard Ghalie, M.D. Richard Ghalie, M.D. Senior DirectorSenior DirectorImmunex CorporationImmunex Corporation

•Clinician’s Clinician’s Fred Lublin, M.D. Fred Lublin, M.D. PerspectivePerspective Professor of Professor of NeurologyNeurology

MCP Hahnemann MCP Hahnemann UniversityUniversity


Study InvestigatorsStudy Investigators

• H. Peter Hartung, MDH. Peter Hartung, MD Chairman, Department of Chairman, Department of NeurologyNeurology

Graz University, AustriaGraz University, AustriaChairman, Study 901Chairman, Study 901

• Erich Mauch, MD Erich Mauch, MD Medical Director, Neurology Medical Director, Neurology Clinic Clinic

Academic Hospital ofAcademic Hospital ofUlm University, Germany Ulm University, Germany Chairman, Study 903Chairman, Study 903

• Gilles Edan, MD Gilles Edan, MD Chairman, Department of Chairman, Department of Neurology Neurology

CHU Rennes, France CHU Rennes, France Chairman, Study 902Chairman, Study 902


Immunex AdvisorsImmunex Advisors

• Hillel Panitch, MDHillel Panitch, MD Professor, Department of Professor, Department of NeurologyNeurology

University of Maryland University of Maryland Baltimore, MDBaltimore, MD

• David Alberts, MDDavid Alberts, MD Professor of Medicine, Professor of Medicine, PharmacologyPharmacology

and Public Healthand Public HealthAssociate Dean for ResearchAssociate Dean for ResearchUniversity of ArizonaUniversity of ArizonaTucson, AZTucson, AZ

• Craig Smith, MDCraig Smith, MD Clinical Professor of Neurology,Clinical Professor of Neurology,Medicine and Ophthalmology Medicine and Ophthalmology University of WashingtonUniversity of WashingtonSeattle, WASeattle, WA


Mitoxantrone in Multiple Sclerosis Mitoxantrone in Multiple Sclerosis (MS)(MS)

Efficacy and Safety ReviewEfficacy and Safety Review


Mitoxantrone in Multiple SclerosisMitoxantrone in Multiple SclerosisData Presentation and DiscussionData Presentation and Discussion

• Efficacy data from 2 randomized trials Efficacy data from 2 randomized trials

• Safety dataSafety data

– Two randomized trials (901-902)Two randomized trials (901-902)

– One retrospective study (903)One retrospective study (903)

– 12+ years post marketing experience12+ years post marketing experience

• Benefit and risk assessmentBenefit and risk assessment

• Discussion of questions raised by Dr. Discussion of questions raised by Dr. KatzKatz


Published Studies of Mitoxantrone Published Studies of Mitoxantrone in MSin MS

Gonsette (1990) Gonsette (1990) 2222 14 q 3 w14 q 3 w

Kappos (1990) Kappos (1990) 1414 10 q 3 w10 q 3 w

Mauch (1992) Mauch (1992) 1010 12 q 3 m12 q 3 m

Noseworthy (1993) Noseworthy (1993) 1313 8 q 3 w 8 q 3 w

Rugerro (1993) Rugerro (1993) 1414 8 q 3 w 8 q 3 w

Millefiorini (1997)Millefiorini (1997) 2727 8 q m x 12 vs. 8 q m x 12 vs. placeboplacebo

TotalTotal 100100 8-14 mg/m8-14 mg/m22 q 3w - q 3w - 3m3m

No. ofNo. of Dose (mg/m Dose (mg/m22) ) AuthorAuthor PatientsPatients Schedule Schedule


Studies in Mitoxantrone Filing Studies in Mitoxantrone Filing in MSin MS

Number of Patients Number of Patients

StudyStudy DesignDesign MitoMito ControlControl TotalTotal

901901 Phase IIIPhase III 127127 6464 191191

902902 Phase IIPhase II 2222 2222 4444

903903 RetrospectiveRetrospective 454454 n/an/a 454454

603603 8686 689689


Study 901Study 901

Design and Efficacy ResultsDesign and Efficacy Results


Study 901 - MIMS TrialStudy 901 - MIMS Trial

• Phase III, randomized, placebo-controlled Phase III, randomized, placebo-controlled studystudy

• 17 centers in 4 European countries17 centers in 4 European countries

• 194 patients 194 patients

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

• Study approved by BfArM/GermanyStudy approved by BfArM/Germany

• June 1993 - July 1997June 1993 - July 1997

ECTRIMS - 1998, 1999 and AAN - 1999ECTRIMS - 1998, 1999 and AAN - 1999


Study 901 - Inclusion CriteriaStudy 901 - Inclusion Criteria

• Age 18 to 55 Age 18 to 55

• MS according to Poser’s criteriaMS according to Poser’s criteria

• Secondary progressive or remittingSecondary progressive or remittingprogressive* MSprogressive* MS

• EDSS progression EDSS progression 1 point in 1 point in precedingpreceding18 months18 months

• Baseline EDSS from 3 to 6Baseline EDSS from 3 to 6

* Relapsing remitting MS with residual deficit after relapse* Relapsing remitting MS with residual deficit after relapse


Kurtzke EDSS Scoring SystemKurtzke EDSS Scoring System

Death from MSDeath from MS

WheelchairWheelchairIntermittent or unilateral Intermittent or unilateral assistance to walk 100 metersassistance to walk 100 meters

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

NormalNormal

1010

77

6655

33

00

Am

bu

lati

on

im

pair

ed

Am

bu

lati

on

im

pair

ed


Study 901 - Exclusion CriteriaStudy 901 - Exclusion Criteria

• Benign or primary progressive MSBenign or primary progressive MS

• Relapse or treatment with corticosteroids Relapse or treatment with corticosteroids in preceding 8 weeksin preceding 8 weeks

• Prior treatment with mitoxantronePrior treatment with mitoxantrone

• Immunosuppressive therapy in precedingImmunosuppressive therapy in preceding9 months9 months

• Cardiac risk factorsCardiac risk factors

• Major medical illnessMajor medical illness


Study 901 - DesignStudy 901 - Design

• Course every 3 months x 24 monthsCourse every 3 months x 24 months

• Follow-up at Month 36Follow-up at Month 36

PlaceboPlacebo

Mitoxantrone 5 mg/mMitoxantrone 5 mg/m22

Mitoxantrone 12 mg/mMitoxantrone 12 mg/m22

RRAANNDDOOMMIIZZEE


Study 901 - Masking Study DrugStudy 901 - Masking Study Drug

• Placebo (methylene blue) to mask patientsPlacebo (methylene blue) to mask patients

• Evaluators of neurologic disabilityEvaluators of neurologic disability

– Trained prior to study initiationTrained prior to study initiation

– Masked to study drugMasked to study drug

– Not involved in patient managementNot involved in patient management

• MRI evaluators masked to study drug and outcomesMRI evaluators masked to study drug and outcomes

• Treating physicians not masked to study drugTreating physicians not masked to study drug

– Drug administration and patient managementDrug administration and patient management

– Evaluation of adverse eventsEvaluation of adverse events

– Assessment and treatment of relapsesAssessment and treatment of relapses


Study 901 - Primary Efficacy Study 901 - Primary Efficacy CriterionCriterion

• Single multivariate testSingle multivariate test** of 5 variables: of 5 variables:

– EDSS change from baselineEDSS change from baseline

– AI change from baselineAI change from baseline

– Number of relapses requiring treatmentNumber of relapses requiring treatment

– Time to first treated relapseTime to first treated relapse

– SNS change from baselineSNS change from baseline

• Mitoxantrone 12 mg/mMitoxantrone 12 mg/m22 vs placebo at vs placebo at = = 0.050.05

* Wei-Lachin procedure (1992)* Wei-Lachin procedure (1992)


Study 901 - Test of Individual Study 901 - Test of Individual Efficacy VariablesEfficacy Variables

• If p If p 0.05 in multivariate test 0.05 in multivariate test

• Then test individual variables in pre-determined Then test individual variables in pre-determined orderorder– EDSSEDSS– Ambulation IndexAmbulation Index– No. of treated relapsesNo. of treated relapses– Time to 1Time to 1stst treated relapse treated relapse– Standardized Neurologic Status scoreStandardized Neurologic Status score

• At At = 0.05 for each endpoint = 0.05 for each endpoint

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

• 60 patients per group, power = 90%60 patients per group, power = 90%


Study 901 - Kurtzke Expanded Study 901 - Kurtzke Expanded Disability Status Scale Disability Status Scale (EDSS)(EDSS)

• 10-point scale with 0.5 point 10-point scale with 0.5 point incrementsincrements

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

• EDSS EDSS 4.5 defined by functional scores 4.5 defined by functional scores

• EDSS EDSS 5.0 defined by ambulation 5.0 defined by ambulation deficitsdeficits


Study 901 - AI and SNS ScalesStudy 901 - AI and SNS Scales

• Ambulation Index (AI)Ambulation Index (AI)– 10-point scale with 1-point increments10-point scale with 1-point increments– Evaluates ambulation deficitsEvaluates ambulation deficits– AI AI 3 = help required for ambulation 3 = help required for ambulation

• Standardized Neurological Status (SNS) scoreStandardized Neurological Status (SNS) score– Developed and used in Germany Developed and used in Germany 10 years 10 years– 99-point scale with 1-point increments99-point scale with 1-point increments– 5 functional systems (supraspinal, paresis, 5 functional systems (supraspinal, paresis,

spasticity, sensorial, bladder)spasticity, sensorial, bladder)– Emphasizes supraspinal evaluation (50 points)Emphasizes supraspinal evaluation (50 points)


Study 901 - Disposition of Study 901 - Disposition of PatientsPatients

RandomizedRandomizedN=194N=194

PlaceboPlacebon=65n=65

Mito 12Mito 12n=63n=63

Mito 5Mito 5n=66n=66

Not treatedNot treatedn=1n=1


Withdrew Withdrew afterafter

1 course1 coursen=1n=1


Withdrew Withdrew afterafter

1 course1 coursen=2n=2

n=64n=64 n=64n=64 n=60n=60


Study 901 - Early Drug Study 901 - Early Drug DiscontinuationDiscontinuation

Number of Patients Number of Patients

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

Lack of efficacy Lack of efficacy 88 33 44

Patient refusalPatient refusal 66 33 22

Lost to follow-upLost to follow-up 11 33 00

Adverse eventAdverse event 22 00 55

OtherOther 00 11 11

Total discontinuedTotal discontinued 1717 1010 1212

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


Study 901 - Baseline Study 901 - Baseline DemographicsDemographics

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

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

Mean age (years)Mean age (years) 4040 4040 4040

Type of MSType of MS

Remittent progressive (%)Remittent progressive (%) 4545 5858 4747

Secondary progressive (%)Secondary progressive (%) 5555 4242 5353


Study 901 - Baseline Study 901 - Baseline DemographicsDemographicsDisease StatusDisease Status

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

Duration of MS (years)Duration of MS (years) 1010 99 1010

No. relapses prior yearNo. relapses prior year 1.31.3 1.41.4 1.31.3

EDSS last 18 monthsEDSS last 18 months 1.6 1.6 1.61.6 1.51.5

EDSS at entryEDSS at entry 4.74.7 4.74.7 4.54.5


Study 901 - Primary Efficacy Study 901 - Primary Efficacy CriterionCriterion

NR = Median not reached within 24 monthsNR = Median not reached within 24 months

p-valuep-valuePlacebo Placebo Mito 5Mito 5 Mito 12Mito 12 Mito 12Mito 12(n=64)(n=64) (n=64)(n=64) (n=60)(n=60) vs Placebovs Placebo

Multivariate primary efficacy criterionMultivariate primary efficacy criterion0.00010.0001

EDSS change (mean)EDSS change (mean) 0.230.23 -0.23-0.23 -0.13-0.130.01940.0194

AI change (mean) AI change (mean) 0.77 0.77 0.410.41 0.300.300.03060.0306

No. treated relapses (adj.) No. treated relapses (adj.) 76.876.8 46.946.9 24.124.10.00020.0002

Time to 1Time to 1stst treated treated

relapse (median, months) relapse (median, months) 14.214.2 NRNR NRNR0.00040.0004

SNS change (mean) SNS change (mean) 0.770.77 -0.38-0.38 -1.07-1.070.02690.0269


Study 901 - Mean Change in Study 901 - Mean Change in EDSSEDSS

†† Mito 12 vs PlaceboMito 12 vs Placebo

-0.3-0.3

-0.2-0.2

-0.1-0.1

0.00.0

0.10.1

0.20.2

0.30.3

0.23

PlaceboPlacebo

-0.23

Mito 5Mito 5

-0.13

p=0.0194p=0.0194††

Mito 12Mito 12

Ch

an

ge M

24

Ch

an

ge M

24 B

aselin

eB

aselin

e


Study 901 - Mean Change in AIStudy 901 - Mean Change in AI

0.00.00.10.10.20.20.30.30.40.40.50.50.60.60.70.70.80.8

Ch

an

ge M

24

Ch

an

ge M

24 B

aselin

eB

aselin

e

0.77

PlaceboPlacebo

0.41

Mito 5Mito 5

0.30

p=0.030p=0.03066††

Mito 12Mito 12



Study 901 - Mean Change in SNS Study 901 - Mean Change in SNS ScoreScore

-1.5-1.5

-1.0-1.0

-0.5-0.5

0.00.0

0.50.5

1.01.0

0.77

PlaceboPlacebo

-0.38

Mito 5Mito 5

-1.07

Mito 12Mito 12

p=0.026p=0.02699††

Ch

an

ge M

24

Ch

an

ge M

24 B

aselin

eB

aselin

e



Study 901 - Total Number Treated Study 901 - Total Number Treated Relapses (Adjusted for Relapses (Adjusted for Dropouts)Dropouts)

76.8

46.9

24.1

00

2020

4040

6060

8080

100100

Ad

juste

d N

o.

of

Rela

pses

Ad

juste

d N

o.

of

Rela

pses

p=0.000p=0.00022††

PlaceboPlacebo Mito 5Mito 5 Mito 12Mito 12

69%



Study 901 - Time to First Treated Study 901 - Time to First Treated RelapseRelapse

0.000.00

0.250.25

0.500.50

0.750.75

1.001.00

p=0.000p=0.00044Mito 12 Mito 12 vs vs PlaceboPlacebo

00 33 66 99 1212 1515 1818 2121 2424MonthsMonths

Pro

port

ion

Even

t-Fre

eP

rop

ort

ion

Even

t-Fre

e PlaceboPlacebo

Mito 5Mito 5

Mito 12Mito 12


Study 901 - Secondary Efficacy Study 901 - Secondary Efficacy VariablesVariables

p-value p-value Placebo Placebo Mito 5Mito 5 Mito 12Mito 12 Mito 12 Mito 12 (n=64)(n=64) (n=64)(n=64) (n=60)(n=60) vs Placebovs Placebo

EDSS 1.0 point increase EDSS 1.0 point increase confirmed 3 months laterconfirmed 3 months later 2222 1414 88 0.0360.036

EDSS 1.0 point increase EDSS 1.0 point increase confirmed 6 months later confirmed 6 months later 1919 99 77 0.0450.045

Patients requiring a wheelchairPatients requiring a wheelchair 1111 88 55 NSNS

Patients without relapsesPatients without relapses 3636 3939 5757 0.0210.021

Overall rating good/very goodOverall rating good/very good 1717 4242 4343 0.0010.001

QOL improvementQOL improvement 2121 4646 4141 0.0070.007

Worsening depression scaleWorsening depression scale 4040 4444 3737 NSNS

Hospitalization other than drug admin.Hospitalization other than drug admin. 6767 5656 40400.0020.002

Patients (%)Patients (%)


Study 901 - Mean Change in Study 901 - Mean Change in EDSSEDSS

Quarterly Months 3 Quarterly Months 3 to 24to 24

Ch

an

ge in

ED

SS

Ch

an

ge in

ED

SS

MonthsMonths

-0.35-0.35

0.050.05

0.250.25

-0.25-0.25

-0.15-0.15

0.150.15

-0.05-0.05

33 66 99 1212 1515 1818 2121 2424

Placebo Placebo

Mito 5Mito 5

Mito 12Mito 12


Study 901 - EDSS Study 901 - EDSS 1.0 Point 1.0 Point DeteriorationDeteriorationSustained for 6 MonthsSustained for 6 Months

00

55

1010

1515

2020

% (

No.)

of

pati

en

ts%

(N

o.)

of

pati

en

ts 19%(n=12

)

PlaceboPlacebo

9%(n=6)

Mito 5Mito 5

7%

p=0.045p=0.045††

(n=4)

Mito 12Mito 12

64%



Study 901 - Categorized Study 901 - Categorized 1.0 Point1.0 PointEDSS ChangeEDSS Change

Number (%) of PatientsNumber (%) of Patients

PlaceboPlacebo Mito 5Mito 5 Mito 12Mito 12ChangeChange (n=64)(n=64) (n=64)(n=64) (n=60)(n=60)

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

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

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

* p=0.013 for Mito 12 vs Placebo* p=0.013 for Mito 12 vs Placebo


Study 901 - Patients Without Study 901 - Patients Without RelapsesRelapses

36% 39%

57%

00

1010

2020

3030

4040

5050

6060

% (

No.)

of

pati

en

ts%

(N

o.)

of

pati

en

ts

(n=23)

(n=25)

(n=34)

p=0.021p=0.021††




Study 901 - Annualized Relapse Study 901 - Annualized Relapse RateRate

p-valuep-valueRelapse Relapse PlaceboPlacebo Mito 5Mito 5 Mito 12Mito 12 Mito 12Mito 12RateRate (n=43)(n=43) (n=53)(n=53) (n=42)(n=42) vs placebovs placebo

BaselineBaseline 1.31.3 1.41.4 1.31.3 NSNS

Year 1Year 1 1.21.2 0.70.7 0.4 0.4 < 0.0001< 0.0001

Year 2Year 2 0.90.9 0.50.5 0.30.3 0.0001 0.0001

Years 1 + 2Years 1 + 2 1.0 1.0 0.60.6 0.40.4 0.0002 0.0002


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

00

0.50.5

11

1.51.5

22

2.52.5

33

3.53.5

EDSSEDSS

Placebo (n=43)Placebo (n=43)

Mito 5 (n=53)Mito 5 (n=53)

Mito 12 (n=42)Mito 12 (n=42)

Mean

Ch

an

ge M

36 -

Baselin

e

Mean

Ch

an

ge M

36 -

Baselin

e

0.460.040.04 0.100.10

SNSSNS

3.28

1.51

0.190.19

AIAI

1.13

0.550.61

* Not masked Months 24 to 36* Not masked Months 24 to 36


Study 901 - Relapse Rate Months 24 Study 901 - Relapse Rate Months 24 to 36*to 36*

Mean

Rela

pses M

on

th 2

4 t

o

Mean

Rela

pses M

on

th 2

4 t

o

36

36

00

0.20.2

0.40.4

0.60.6

0.80.8

All RelapsesAll Relapses Treated RelapsesTreated Relapses

0.33

0.56

0.33

0.46

0.77

0.50

Placebo (n=43)Placebo (n=43)

Mito 5 (n=52)Mito 5 (n=52)

Mito 12 (n=42)Mito 12 (n=42)



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

PlaceboPlacebo

Mito 5Mito 5

Mito 12Mito 12

0.00.0

0.20.2

0.40.4

0.60.6

0.80.8

1.01.0

MonthsMonths

Pro

port

ion

Even

t-Fre

eP

rop

ort

ion

Even

t-Fre

e

00 66 1212 1818 2424 3030 3636

DiscontinuationDiscontinuationof study drugof study drug



Study 901 - Clinical Efficacy Study 901 - Clinical Efficacy ConclusionsConclusions

• Mitoxantrone 12 mg/mMitoxantrone 12 mg/m22 vs placebo: vs placebo:

– Slows neurologic disabilitySlows neurologic disability 1.0 point EDSS -- 64%1.0 point EDSS -- 64%

– Decreases relapse rateDecreases relapse rate treated relapses -- 69%treated relapses -- 69%

• No disease rebound 1 year after treatmentNo disease rebound 1 year after treatmentdiscontinuationdiscontinuation

• Dose response effectDose response effect


Study 901 - MRI Subgroup Study 901 - MRI Subgroup EvaluationEvaluation

• T1-w Gd-enhanced and T2-w scansT1-w Gd-enhanced and T2-w scans

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

• 110 patients in specified sites110 patients in specified sites

• MRI review:MRI review:

– Centrally at the end of the studyCentrally at the end of the study

– Evaluators masked to study drug and Evaluators masked to study drug and clinical outcomesclinical outcomes


Study 901 - Patients with Study 901 - Patients with Gd-Enhancing LesionsGd-Enhancing Lesions

% (

No.)

of

Pati

en

ts%

(N

o.)

of

Pati

en

ts

PlaceboPlacebo

Mito 12Mito 12

29%29%

22%22%

15%15%19%19%

3%3%

16%16%

00

1010

2020

3030

4040

(n=8)

(n=7)(n=5)

(n=10)

(n=5)

(n=1)

1212 242400 1212 242400

MonthMonth

p=0.105 p=0.105 at Month at Month 2424


Study 901 - Patients with New Study 901 - Patients with New Gd-Enhancing LesionsGd-Enhancing Lesions

12%12%

19%19%

0%0%

16%16%

00

5

1010

1515

2020

% (

No.)

of

Pati

en

ts%

(N

o.)

of

Pati

en

ts

PlaceboPlacebo

Mito 12Mito 12

1212 2424 1212 2424MonthMonth

(n=7)

(n=5)

(n=4)

(n=0)(n=0)



Study 901 - Change in Total T2-Study 901 - Change in Total T2-Weighted Lesion Load Weighted Lesion Load (Score 1 - 5)(Score 1 - 5)

0.580.58

2.362.36

0.640.64

4.284.28

00

1

22

33

44

55

Mean

Score

Ch

an

ge

Mean

Score

Ch

an

ge

PlaceboPlacebo

Mito 12Mito 12

1212 2424 1212 2424MonthMonth



Study 901 - MRI Efficacy Study 901 - MRI Efficacy ConclusionsConclusions

• Mitoxantrone Mitoxantrone

– Decreased Gd-enhancing lesionsDecreased Gd-enhancing lesions

– Slowed progression of T2-w lesion Slowed progression of T2-w lesion loadload

• Indicates a reduction of inflammation Indicates a reduction of inflammation in CNSin CNS

• Support clinical findings of studySupport clinical findings of study


Study 902Study 902

Design and Efficacy ResultsDesign and Efficacy Results


Study 902 - Phase II Trial in Study 902 - Phase II Trial in Active MSActive MS

• Randomized, corticosteroid-controlled trialRandomized, corticosteroid-controlled trial

• 5 academic centers in France5 academic centers in France

• 44 patients 44 patients

• Chair - Professor G. EdanChair - Professor G. Edan

• April 1992 - March 1995April 1992 - March 1995

Journal of Neurology, Neurosurgery and Psychiatry Journal of Neurology, Neurosurgery and Psychiatry 19971997


Study 902 - Inclusion CriteriaStudy 902 - Inclusion Criteria

•Age 18 to 45 Age 18 to 45

•Disease history of less than 10 yearsDisease history of less than 10 years

•Highly active diseaseHighly active disease

– EDSS progression EDSS progression 2 points 2 points

– Or Or 2 relapses 2 relapses

– In preceding 12 monthsIn preceding 12 months

•Baseline EDSS Baseline EDSS 6.0 6.0


Study 902 - Exclusion CriteriaStudy 902 - Exclusion Criteria

•Corticosteroids in previous monthCorticosteroids in previous month

• Immunosuppressive therapy in Immunosuppressive therapy in previous 3 monthsprevious 3 months

•Cardiac risk factors or major Cardiac risk factors or major illnessillness

•Pregnancy or breast feedingPregnancy or breast feeding


Study 902 - DesignStudy 902 - Design

TriageTriage

M -2M -2 M -1M -1 M 0M 0

M 1M 1 M 2M 2 M 3M 3 M 4M 4 M 5M 5 M 6M 6

M 1M 1 M 2M 2 M 3M 3 M 4M 4 M 5M 5 M 6M 6

Randomized TreatmentRandomized Treatment

methylprednisolone 1 g/month IVmethylprednisolone 1 g/month IV

mitoxantrone 20 mg/month IVmitoxantrone 20 mg/month IV+ methylprednisolone 1 g/month IV+ methylprednisolone 1 g/month IV


Study 902 - Efficacy EvaluationsStudy 902 - Efficacy Evaluations

•Monthly MRIMonthly MRI

– MRI evaluators masked to study MRI evaluators masked to study drug and outcomedrug and outcome

•Monthly clinical evaluationsMonthly clinical evaluations

– Treating physicians not maskedTreating physicians not maskedto study drugto study drug

– Evaluated EDSS, relapses, Evaluated EDSS, relapses, safetysafety


Study 902 - Study EndpointsStudy 902 - Study Endpoints

• Primary MRI endpoint* Primary MRI endpoint* – Number of patients with new Gd+ Number of patients with new Gd+

lesions monthly x 6lesions monthly x 6• Secondary MRI endpointSecondary MRI endpoint

– Number of new Gd+ lesions monthly x 6Number of new Gd+ lesions monthly x 6• Secondary clinical endpoints Secondary clinical endpoints

– EDSSEDSS– RelapseRelapse

• Main comparisons at Month 6Main comparisons at Month 6

* Miller et al, 1991* Miller et al, 1991


Study 902 - Patient DispositionStudy 902 - Patient Disposition

WithdrewWithdrewafter 1 doseafter 1 dose

n=1n=1

WithdrewWithdrewLoELoEn=5n=5

WithdrewWithdrewafter 1 doseafter 1 dose

n=1n=1

RandomizedRandomizedn=44n=44

Mito + mPMito + mPn=22n=22

Mito + mP Mito + mP completed studycompleted study

n=21n=21

mP mP completed studycompleted study

n=16n=16

mPmPn=22n=22



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

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

Mean age (years) Mean age (years) 3232 3131

Mean duration of MS (years) Mean duration of MS (years) 5.75.76.96.9

No. RRMS/SPMSNo. RRMS/SPMS 15/615/6 17/417/4

Mean relapses in Mean relapses in preceding 12 months preceding 12 months 2.92.9 3.13.1

Mean EDSSMean EDSS 4.74.7 4.44.4RRMS = Relapsing-remitting MS based on RRMS = Relapsing-remitting MS based on 2 relapses. 2 relapses.SPMS = Secondary progressive MS based on SPMS = Secondary progressive MS based on 2.0 points EDSS 2.0 points EDSS increase.increase.


Study 902 - Patients With New Study 902 - Patients With New Gd-Enhancing LesionsGd-Enhancing Lesions

mPmP

Mito + Mito + mPmP

00

2020

4040

6060

8080

100100

% o

f p

ati

en

ts%

of

pati

en

ts

-1-1 00 11 22 33 665544

MonthMonth

*

† ‡ §

* * p=0.009p=0.009† † p=0.030 p=0.030

‡ ‡ p=0.033p=0.033

§ § p=0.001p=0.001

86%


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

Nu

mb

er

of

new

Gd

+ L

esio

ns

Nu

mb

er

of

new

Gd

+ L

esio

ns

00

55

1010

1515

2020

-1-1 00 11 22 33 665544

MonthMonth

p=0.001p=0.001at Month at Month 66

mPmP

Mito + Mito + mPmP


Study 902 - Mean (±SEM) EDSS Study 902 - Mean (±SEM) EDSS Change Change

Mean

ED

SS

Ch

an

ge

Mean

ED

SS

Ch

an

ge

-2-2

-1-1

00

11

22

00 11 22 33 665544

MonthMonth

p=0.013p=0.013at Month at Month 66

mPmP

Mito + Mito + mPmP


Study 902 - Categorized Study 902 - Categorized 1.0 1.0 Point EDSS ChangePoint EDSS Change

mPmP Mito + mPMito + mPChangeChange (n=21)(n=21) (n=21)(n=21) p-valuep-value

Worsened Worsened 6 (29%)6 (29%) 1 (5%)1 (5%) 0.0380.038

StableStable 12 (57%)12 (57%) 8 (38%)8 (38%) 0.2170.217

ImprovedImproved 3 (14%)3 (14%) 12 (57%)12 (57%) 0.0040.004


Study 902 - Relapse Study 902 - Relapse AssessmentAssessment

mPmP Mito + mPMito + mP (n=21)(n=21) (n=21)(n=21) p-valuep-value

Baseline annualizedBaseline annualized 2.92.9 3.13.1 NSNS relapse raterelapse rate

On study annualized On study annualized 3.03.0 0.70.7 0.0030.003

relapse rate relapse rate

Patients free of Patients free of 7 (33%)7 (33%) 14 (67%)14 (67%) 0.0310.031

relapses on study relapses on study


Study 902 - Efficacy ConclusionsStudy 902 - Efficacy Conclusions

• Mitoxantrone + mP vs mP aloneMitoxantrone + mP vs mP alone

– Decreases number of patients with Decreases number of patients with newnewGd+ lesions (86%)Gd+ lesions (86%)

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

– Decreases relapse rate (77%)Decreases relapse rate (77%)


Mitoxantrone Safety DataMitoxantrone Safety Data


Mitoxantrone Safety ExperienceMitoxantrone Safety Experience

StudyStudy DescriptionDescription PatientsPatients

901901 Phase III randomized, controlledPhase III randomized, controlled127127

902902 Phase II randomized, controlledPhase II randomized, controlled 2222

903903 10 year retrospective study10 year retrospective study454454

TotalTotal 603603


Study 901 - Discontinuation Due Study 901 - Discontinuation Due to AEto AE

GroupGroup MonthMonth Reason for Withdrawal Reason for Withdrawal

Mito 12Mito 12** 1818 Nausea and emesisNausea and emesis(n=5)(n=5) 33 DepressionDepression

1212 LVEF LVEF 10% from baseline 10% from baseline1212 Urinary tract infection Urinary tract infection 1818 Renal failure after retention Renal failure after retention

Mito 5 Mito 5 00 ——

PlaceboPlacebo 1515 Myocardial infarction Myocardial infarction (n=2)(n=2) 1818 Liver function abnormalities Liver function abnormalities

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


Study 901 - Clinical Adverse Events More Study 901 - Clinical Adverse Events More Frequent (pFrequent (p0.05) in Either 0.05) in Either Mitoxantrone GroupMitoxantrone Group

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

NauseaNausea 2020 5555 7676

AlopeciaAlopecia 3131 3838 6161

UTIUTI 1313 2929 3232

Menstrual disorderMenstrual disorder 2626 5151 6161

AmenorrheaAmenorrhea 33 2828 6363

% of Patients% of Patients

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


Study 901 - Clinical Adverse Study 901 - Clinical Adverse Events inEvents in 10% of Patients 10% of Patients

PlaceboPlacebo Mito 5Mito 5 Mito 12Mito 12Adverse EventAdverse Event (n=64)(n=64) (n=65)(n=65) (n=62)(n=62)

NauseaNausea 2020 5555 7676AlopeciaAlopecia 3131 3838 6161Urinary tract infectionUrinary tract infection 1313 2929 3232Upper respiratory tract infectionUpper respiratory tract infection 5252 5151 5353StomatitisStomatitis 88 1515 1919ArrhythmiaArrhythmia 88 66 1818DiarrheaDiarrhea 1111 2525 1616Urine abnormalUrine abnormal 66 55 1111ECG abnormalECG abnormal 33 55 1111ConstipationConstipation 66 1414 1010RhinitisRhinitis 1414 1111 88Menstrual disorderMenstrual disorder 2626 5151 6161AmenorrheaAmenorrhea 33 2828 6363

% of Patients% of Patients


Study 901 - Cardiac MonitoringStudy 901 - Cardiac Monitoring

• Clinical evaluation before each courseClinical evaluation before each course

• ECG before each courseECG before each course

• Echocardiogram at baseline, Years 1, 2, Echocardiogram at baseline, Years 1, 2, 33


Study 901 - Number of Patients Study 901 - Number of Patients with LVEF with LVEF 50% 50%


Year 1Year 1 0/640/64 1/641/64 2/592/59

Year 2Year 2 1/471/47 1/541/54 1/521/52

Year 3Year 3 0/350/35 1/441/44 1/361/36

Number of PatientsNumber of Patients

No congestive heart failureNo congestive heart failure


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


Mito 5Mito 5 Mito 12Mito 12LVEF Change LVEF Change (n=43)(n=43) (n=36)(n=36)

Worsened from Worsened from 11 11 50% to 50% to 50% 50%

Improved from Improved from 11 00 50% to 50% to 50% 50%

No congestive heart failureNo congestive heart failure


Study 901 - Additional Safety Study 901 - Additional Safety InformationInformation

• No deathsNo deaths

• Pregnancy: 2 reportedPregnancy: 2 reported

– 1 placebo - terminated pregnancy1 placebo - terminated pregnancy

– 1 mitoxantrone 12 mg/m1 mitoxantrone 12 mg/m22 - normal - normal child child


Study 901 - Hematology Results Study 901 - Hematology Results Normal*Normal*


HemoglobinHemoglobin 1414 1515 1414

PlateletsPlatelets 33 55 66

WBCWBC 55 1515 2020


* Any grade, all reversible. * Any grade, all reversible. No transfusions.No transfusions.No difference in incidence of severe infections No difference in incidence of severe infections and hospitalizations for infection in the 3 and hospitalizations for infection in the 3 groups.groups.


Study 901 - Serum Chemistries Study 901 - Serum Chemistries Normal*Normal*


CreatinineCreatinine 77 66 77

BilirubinBilirubin 1515 1313 1010

GGTGGT 2020 1919 1919

SGOTSGOT 1111 1919 2020

Alkaline phos.Alkaline phos. 88 88 55


* Any grade, all reversible.* Any grade, all reversible.


Study 902 - Adverse EventsStudy 902 - Adverse Events

• Profile similar to Study 901Profile similar to Study 901

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

• No deaths on studyNo deaths on study

• No cardiac toxicity (echocardiogram at No cardiac toxicity (echocardiogram at baseline and M6)baseline and M6)


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

WBC WBC 2,000/µL 2,000/µL 4848

ANC ANC 1,000/µL 1,000/µL 8686

Hemoglobin Hemoglobin 10 g/dL 10 g/dL 00

Platelets Platelets 100,000/µL 100,000/µL 00

% of Patients% of Patients(n=21)(n=21)

* Nadir leukopenia Week 1 or 2* Nadir leukopenia Week 1 or 2


Study 903 - Long Term Safety Study 903 - Long Term Safety DatabaseDatabase

• Academic Clinic of Ulm University, Academic Clinic of Ulm University, GermanyGermany

• Professor Erich MauchProfessor Erich Mauch

• Retrospective analysisRetrospective analysis

• Mitoxantrone given between 11/88 and Mitoxantrone given between 11/88 and 9/989/98

• 454 patients454 patients

• All patients includedAll patients includedECTRIM - 1999ECTRIM - 1999


Study 903 - Data Collection andStudy 903 - Data Collection andQuality AssuranceQuality Assurance

• Staff hired exclusively for data collectionStaff hired exclusively for data collection

• Collection of specified safety andCollection of specified safety andefficacy dataefficacy data

• Attempt to obtain most recent follow-upAttempt to obtain most recent follow-up

• Information on treatment off site not Information on treatment off site not collectedcollected

• All CRFs reviewed by Dr. Mauch for All CRFs reviewed by Dr. Mauch for accuracyaccuracy


Study 903 - Treatment Study 903 - Treatment GuidelinesGuidelines

• Mitoxantrone 12 mg/mMitoxantrone 12 mg/m22 every 3 months every 3 months

• Dose adjustment or interval change as Dose adjustment or interval change as neededneeded

• Treatment discontinued if:Treatment discontinued if:

– Not toleratedNot tolerated

– Good disease responseGood disease response

– Attempt to become pregnantAttempt to become pregnant



ParameterParameter (454 (454 patients)patients)

Mean years since onset of MS Mean years since onset of MS 9.19.1

No. females (%)No. females (%) 276 (61%)276 (61%)

At start of mitoxantrone treatment:At start of mitoxantrone treatment:

Mean age (range) Mean age (range) 37 (15-72)37 (15-72)

Mean no. relapsesMean no. relapsesin preceding 12 months in preceding 12 months 1.021.02

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

Mean EDSS deterioration Mean EDSS deterioration in preceding 12 months in preceding 12 months 0.790.79

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


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

32%32%40%40%

18%18%

00

2020

4040

6060

8080

100100

% (

No.)

of

Pati

en

ts%

(N

o.)

of

Pati

en

ts

(n=144)(n=181

)

(n=80)

1-21-2 3-53-5 6-86-8 99

11%11%

(n=49)

No. of DosesNo. of Doses


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

Number of Number of Cause of Death Cause of Death PatientsPatients

InfectionsInfections 99

Respiratory failureRespiratory failure 55

Heart failure Heart failure 22

CachexiaCachexia 11

Unknown - late deathsUnknown - late deaths 33

TotalTotal 20 (4%)20 (4%)


Study 903 - PregnanciesStudy 903 - Pregnancies

• PregnanciesPregnancies

– 4 during mitoxantrone treatment4 during mitoxantrone treatment

– 5 after discontinuing treatment5 after discontinuing treatment

• BirthsBirths

– 6 normal6 normal

– 1 pregnant at data collection1 pregnant at data collection

– 2 outcomes not available2 outcomes not available


Study 903 - Cardiac Study 903 - Cardiac AbnormalitiesAbnormalities

CycleCycle MitoxantroneMitoxantroneofof Cumulative Cumulative

Type of EventType of Event No.No. EventEvent Dose (mg/mDose (mg/m22))

Decreased LVEFDecreased LVEF 55 7-127-12 50-13050-130

ArrhythmiaArrhythmia 11 11 1111

Mitral valve insuf.Mitral valve insuf. 11 44 4141


Mitoxantrone Cardiac Effects in Mitoxantrone Cardiac Effects in Cancer Patients*Cancer Patients*

• Mitoxantrone given every 3-4 weeksMitoxantrone given every 3-4 weeks

• Often with other chemotherapy/chest Often with other chemotherapy/chest radiationradiation

• At cumulative dose of 140 mg/mAt cumulative dose of 140 mg/m22

– Congestive heart failure = 2.6%Congestive heart failure = 2.6%

– Moderate to severe Moderate to severe LVEF = 13% LVEF = 13%

• Occur during or within a year of Occur during or within a year of completing mitoxantrone therapycompleting mitoxantrone therapy

* Published literature and Immunex databases* Published literature and Immunex databases


Mitoxantrone Safety Mitoxantrone Safety ConclusionsConclusions

• Adverse events mild or moderateAdverse events mild or moderate

• Manageable and reversibleManageable and reversible

• Dose up to 100 mg/mDose up to 100 mg/m22 in MS trials not in MS trials not associated with congestive heart failureassociated with congestive heart failure

• MyelosuppressionMyelosuppression

– Reversible within 1 - 3 weeksReversible within 1 - 3 weeks

– Not associated with severe infectionNot associated with severe infection

• No secondary leukemia or myelodysplasiaNo secondary leukemia or myelodysplasia


Risk & Benefit AssessmentRisk & Benefit Assessment

• Well characterized adverse events Well characterized adverse events

– MonitoringMonitoring

– ManagementManagement

• Clear benefit in progressive MSClear benefit in progressive MS

• Benefits outweigh risksBenefits outweigh risks

– Disease stage without satisfactory Disease stage without satisfactory therapytherapy


Acute Adverse EventsAcute Adverse Events

• Mild to moderate intensityMild to moderate intensity

• Nausea and emesis: transient, manageableNausea and emesis: transient, manageable

• Alopecia mild, reversibleAlopecia mild, reversible

• Leukopenia Leukopenia

– Grade 3-4 in Grade 3-4 in 50% of patients 50% of patients

– Between day 7-14Between day 7-14

– Reversible by day 21Reversible by day 21

– Risk of neutropenic fever lowRisk of neutropenic fever low


Laboratory MonitoringLaboratory Monitoring

• Serum chemistries (including LFT)Serum chemistries (including LFT)

– Before each courseBefore each course

• HemogramHemogram

– Before each courseBefore each course

– If fever develops at expectedIf fever develops at expectedleukocyte nadir leukocyte nadir


Cardiac MonitoringCardiac Monitoring

• LVEF assessmentLVEF assessment– At baselineAt baseline– At cumulative dose of 100 mg/mAt cumulative dose of 100 mg/m22

• Assess risk/benefit and monitor LVEFAssess risk/benefit and monitor LVEFbefore each course if:before each course if:– Cumulative dose Cumulative dose 100 mg/m 100 mg/m22

– LVEF decreases by LVEF decreases by 15% from baseline 15% from baseline

• Discontinue therapy if:Discontinue therapy if:– LVEF LVEF 50% 50% – Cumulative dose Cumulative dose 140 mg/m 140 mg/m22


PregnancyPregnancy

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


Benefit of Mitoxantrone - Study Benefit of Mitoxantrone - Study 901901

• Slows progression of neurologic impairment Slows progression of neurologic impairment – Decreases 1.0 EDSS progression by 64%Decreases 1.0 EDSS progression by 64%

• Reduces relapsesReduces relapses– Decreases treated relapses by 69%Decreases treated relapses by 69%

• Lessens CNS lesionsLessens CNS lesions– Substantial decrease in number of Substantial decrease in number of

patients with Gd-enhanced lesionspatients with Gd-enhanced lesions– Slows progression of T2w lesionsSlows progression of T2w lesions


Benefit of Mitoxantrone - Benefit of Mitoxantrone - Supportive StudiesSupportive Studies

• Study 902 (mP vs Mitoxantrone + mP)Study 902 (mP vs Mitoxantrone + mP)

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

– Decreases relapse rate (77%)Decreases relapse rate (77%)

– Decreases number of patients with newDecreases number of patients with newGd+ lesions (86%)Gd+ lesions (86%)

• Study 903Study 903

– Therapy feasible in practice settingTherapy feasible in practice setting


DiscussionDiscussion


Adequacy of Controlled Study Adequacy of Controlled Study 901901

•Well designed, randomized, Well designed, randomized, placebo-controlledplacebo-controlled

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

• Effect on disability and relapse Effect on disability and relapse using established scalesusing established scales

•MRI prospectively limited to subsetMRI prospectively limited to subset


Adequacy of Controlled Study Adequacy of Controlled Study 902902

•Well designed, randomized, Well designed, randomized, controlledcontrolled

•Prospectively defined entry Prospectively defined entry criteria, endpointscriteria, endpoints

•Design typical of MRI-based trialDesign typical of MRI-based trial

• Effect on disability and relapse Effect on disability and relapse using established scalesusing established scales


Mitoxantrone Slows Mitoxantrone Slows Progression of Neurologic Progression of Neurologic Disability - Study 901Disability - Study 901

•Used 3 complementary disability Used 3 complementary disability scalesscales

•All 3 primary disability endpoints All 3 primary disability endpoints metmet

• Secondary disability endpoints metSecondary disability endpoints met

•No rebound one year after No rebound one year after stopping therapystopping therapy


Mitoxantrone Slows Mitoxantrone Slows Progression of Neurologic Progression of Neurologic Disability - Study 902Disability - Study 902

• EDSS assessment unmaskedEDSS assessment unmasked

•Results robustResults robust

– Significant difference between Significant difference between mitoxantrone and controlmitoxantrone and control

– Consistency of EDSS results in Consistency of EDSS results in thethe2 randomized studies2 randomized studies


Mitoxantrone Decreases Mitoxantrone Decreases RelapseRelapse

•Relapse definition/severityRelapse definition/severity

– prospectively defined in both prospectively defined in both studiesstudies

•Consistency of results in the 2 Consistency of results in the 2 studiesstudies

•Highly significant vs control groupHighly significant vs control group

•Consistency in all relapse Consistency in all relapse evaluationsevaluations


MRI Results - Study 901MRI Results - Study 901

•MRI evaluationsMRI evaluations– In subset of patientsIn subset of patients– No stratification by baseline MRINo stratification by baseline MRI– Study not sized for MRI endpointsStudy not sized for MRI endpoints

•Decreased Gd+ lesions Decreased Gd+ lesions – Consistent with clinical resultsConsistent with clinical results– Suggests biologic effectSuggests biologic effect


MRI Results - Study 902MRI Results - Study 902

•Design typical of MRI-based trialDesign typical of MRI-based trial

•Nine monthly scans per patientNine monthly scans per patient

•MRI findingsMRI findings

– Highly significantHighly significant

– Consistent with clinical resultsConsistent with clinical results

– Indicate mitoxantrone biologic effectIndicate mitoxantrone biologic effect

•Consistent MRI results in both studiesConsistent MRI results in both studies


Dose - 12 mg/mDose - 12 mg/m22 Every 3 Every 3 MonthsMonths

• Investigational dose in Study 901Investigational dose in Study 901

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

•Dose of 20 mg (Study 902) Dose of 20 mg (Study 902) 12 mg/m 12 mg/m22

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


Target PopulationTarget Population

•Patients with progressive forms of Patients with progressive forms of MS excluding primary progressive MS excluding primary progressive MSMS


Mitoxantrone in Multiple Mitoxantrone in Multiple Sclerosis:Sclerosis:

A Clinician’s PerspectiveA Clinician’s Perspective

Fred D. Lublin, M.D.Fred D. Lublin, M.D.Professor of NeurologyProfessor of Neurology

MCP Hahnemann UniversityMCP Hahnemann University


Clinical Courses of MSClinical Courses of MSIn

cre

asin

g D

isab

ilit

yIn

cre

asin

g D

isab

ilit

y

TimeTime

RelapsingRelapsingremittingremitting

Secondary Secondary progressiveprogressive

Primary Primary progressiveprogressive

ProgressiveProgressiverelapsingrelapsing


Mechanisms of Worsening of Mechanisms of Worsening of MSMS

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

• Gradual, progressive worsening Gradual, progressive worsening independent of relapsesindependent of relapses


Mechanisms of Worsening of Mechanisms of Worsening of MSMS


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

Incre

asin

g D

isab

ilit

yIn

cre

asin

g D

isab

ilit

y

TimeTime

RelapsingRelapsingremittingremitting

ProgressiveProgressiverelapsingrelapsing

Secondary Secondary progressiveprogressive


ConclusionsConclusions


Effectiveness of Mitoxantrone Effectiveness of Mitoxantrone in MSin MS


– Primary endpoint - clinicalPrimary endpoint - clinical

– MRI data consistent with clinical MRI data consistent with clinical findingsfindings


– Primary endpoint - MRIPrimary endpoint - MRI

– Clinical data consistent with MRI Clinical data consistent with MRI findingsfindings


Proposed Use of Mitoxantrone in Proposed Use of Mitoxantrone in MSMS

• To slow progression of neurologic To slow progression of neurologic disability and reduce relapse ratedisability and reduce relapse rate

•Patients with progressive forms of MS Patients with progressive forms of MS excluding primary progressive MSexcluding primary progressive MS

•Dose 12 mg/mDose 12 mg/m2 2 every 3 monthsevery 3 months

•Disease control for 2-3 years beneficialDisease control for 2-3 years beneficial

•Patients with limited therapeutic Patients with limited therapeutic optionsoptions

novantrone main presentation version 7.0 - 10/3/2015 m-1 mitoxantrone for multiple sclerosis...

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