# Presentation: 191208

## Peripheral & Central Nervous System DrugsAdvisory Committee	        January 28, 2000

**(Novantrone****®****)**

**Immunex Corporation**** **

**Peripheral & Central Nervous System Drugs****Advisory Committee****	****        January 28, 2000**

## Mitoxantrone Approved Indications

**Adult acute myeloid leukemia (1987)**
**12 mg/m****2****/day x 3 days every 4-6 weeks**
**Symptomatic hormone-refractory prostate cancer (1996)**
**12-14 mg/m****2**** every 3 weeks**

## 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/m****2****/day x 3 days every 4-6 weeks**
**8-14 mg/m****2**** repeated every 3-4 weeks**
**30-80 mg/m****2**** single dose **
**Alone or in combination with other drugs**
**Well characterized safety profile**

## 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

**Antiproliferative effects -- reduces**
**B-lymphocytes**
**T-lymphocytes**
**Macrophages**
**Immunomodulatory effects**
**Decreases antigen presentation**
**Decreases cytokine production ****(IL-2, TNF********, IFN********)**

## 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

**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

**“****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

**Introduction****	****Ann Hayes, M.D.****	****Senior Vice President****	****Immunex Corporation**

**Efficacy & Safety**** ****	****Richard Ghalie, M.D. ****	****Senior Director****	****Immunex Corporation**

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

## Study Investigators

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

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

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

## Immunex Advisors

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

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

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

## Mitoxantrone in Multiple Sclerosis (MS)

**Efficacy and Safety Review**

## Mitoxantrone in Multiple SclerosisData 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

**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/m****2**** q 3w - 3m**

**	****No. of****	**** Dose (mg/m****2****) ****Author****	****Patients****	**** Schedule**

## 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Design and Efficacy Results

## 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

**Age 18 to 55 **
**MS according to Poser’s criteria**
**Secondary progressive or remitting****progressive* MS**
**EDSS progression ******** 1 point in preceding****18 months**
**Baseline EDSS from 3 to 6**

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

## Kurtzke EDSS Scoring System

**Death from MS**

**Wheelchair**

**Intermittent or unilateral assistance to walk 100 meters**

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

**Normal**

**Ambulation impaired**

## 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 preceding****9 months**
**Cardiac risk factors**
**Major medical illness**

## Study 901 - Design

**Course every 3 months x 24 months**
**Follow-up at Month 36**

**Placebo**

**Mitoxantrone 5 mg/m****2**

**Mitoxantrone 12 mg/m****2**** **

**R**
**A**
**N**
**D**
**O**
**M**
**I**
**Z**
**E**

## 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

**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/m****2**** vs placebo at ******** = 0.05**

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

## 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 1****st**** 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)

**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

**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

**Randomized****N=194**

**Placebo**
**n=65**

**Mito 12**
**n=63**

**Mito 5**
**n=66**

**Not treated**
**n=1**

**Not treated**
**n=1**

**Withdrew ****after**
**1 course**
**n=1**

**Not treated**
**n=1**

**Withdrew ****after**
**1 course**
**n=2**

**n=64**

**n=64**

**n=60**

## Study 901 - Early Drug Discontinuation

**	****	****Number of Patients **
**	****Placebo ****	****Mito 5****	****Mito 12****Reason 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

## Study 901 - Baseline DemographicsDisease Status

**	****Placebo ****	****Mito 5****	****Mito 12****Mean 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 Criterion

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

**	****	****	****	**** ****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 1****st**** treated**** ****	****relapse (median, months) ****	****14.2****	****NR****	****NR****	****0.0004**
**   ****SNS change (mean) ****	****0.77****	****-0.38****	****-1.07****	****0.0269**

## Study 901 - Mean Change in EDSS

**†**** ****Mito 12 vs Placebo**

**-0.3**

**-0.2**

**-0.1**

**0.0**

**0.1**

**0.2**

**0.3**

**0.23**

**Placebo**

**-0.23**

**Mito 5**

**-0.13**

**p=0.0194****†**

**Mito 12**

**Change M24 ********Baseline**

## Study 901 - Mean Change in AI

**0.0**

**0.1**

**0.2**

**0.3**

**0.4**

**0.5**

**0.6**

**0.7**

**0.8**

**Change M24 ********Baseline**

**0.77**

**Placebo**

**0.41**

**Mito 5**

**0.30**

**p=0.0306****†**

**Mito 12**

**†**** ****Mito 12 vs Placebo**

## Study 901 - Mean Change in SNS Score

**-1.5**

**-1.0**

**-0.5**

**0.0**

**0.5**

**1.0**

**Change M24 ********Baseline**

**†**** ****Mito 12 vs Placebo**

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

**76.8**

**46.9**

**24.1**

**0**

**20**

**40**

**60**

**80**

**100**

**Adjusted No. of Relapses**

**p=0.0002****†**

**Placebo**

**Mito 5**

**Mito 12**

**69%**

**†**** ****Mito 12 vs Placebo**

## Study 901 - Time to First Treated Relapse

**0.00**

**0.25**

**0.50**

**0.75**

**1.00**

**p=0.0004**
**Mito 12 vs Placebo**

**0**

**3**

**6**

**9**

**12**

**15**

**18**

**21**

**24**

**Months**

**Proportion Event-Free**

**Placebo**

**Mito 5**

**Mito 12**

## Study 901 - Secondary Efficacy Variables

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

**Change in EDSS**

**Months**

**-0.35**

**0.25**

**-0.25**

**-0.15**

**0.15**

**3**

**6**

**9**

**12**

**15**

**18**

**21**

**24**

## Study 901 - EDSS  1.0 Point DeteriorationSustained for 6 Months

**0**

**5**

**10**

**15**

**20**

**% (No.) of patients**

**19%**

**(n=12)**

**Placebo**

**9%**

**(n=6)**

**Mito 5**

**7%**

**p=0.045****†**

**(n=4)**

**Mito 12**

**64%**

**†**** ****Mito 12 vs Placebo**

## Study 901 - Categorized  1.0 PointEDSS 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

**36%**

**39%**

**57%**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**% (No.) of patients**

**(n=23)**

**(n=25)**

**(n=34)**

**p=0.021****†**

**Placebo**

**Mito 5**

**Mito 12**

**†**** ****Mito 12 vs Placebo**

## Study 901 - Annualized Relapse Rate

**	****	****	****	****p-value****Relapse ****	****Placebo****	****Mito 5****	****Mito 12****	****Mito 12****Rate****	****(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*

**0**

**0.5**

**1**

**1.5**

**2**

**2.5**

**3**

**3.5**

**EDSS**

**Placebo (n=43)**

**Mito 5    (n=53)**

**Mito 12  (n=42)**

**Mean Change M36 - Baseline **

**0.46**

**0.04**

**0.10**

**SNS**

**3.28**

**1.51**

**0.19**

**AI**

**1.13**

**0.55**

**0.61**

*** Not masked Months 24 to 36**

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

**Mean Relapses Month 24 to 36**

**0**

**0.2**

**0.4**

**0.6**

**0.8**

**All Relapses**

**Treated Relapses**

**0.33**

**0.56**

**0.33**

**0.46**

**0.77**

**0.50**

**Placebo  (n=43)**

**Mito 5     (n=52)**

**Mito 12   (n=42)**

*** Not masked Months 24 to 36**

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

**Placebo**

**0.0**

**0.2**

**0.4**

**0.6**

**0.8**

**1.0**

**Months**

**Proportion Event-Free**

**Discontinuation****of study drug**

*** Not masked Months 24 to 36**

## Study 901 - Clinical Efficacy Conclusions

**Mitoxantrone 12 mg/m****2**** vs placebo: **
**Slows neurologic disability**
**1.0 point EDSS -- 64%**
**Decreases relapse rate**
**treated relapses -- 69%**
**No disease rebound 1 year after treatment****discontinuation**
**Dose response effect**

## 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

**% (No.) of Patients**

**Placebo**

**Mito 12**

**29%**

**22%**

**15%**

**19%**

**3%**

**16%**

**0**

**10**

**20**

**30**

**40**

**(n=8)**

**(n=7)**

**(n=5)**

**(n=10)**

**(n=5)**

**(n=1)**

**12**

**24**

**0**

**12**

**24**

**0**

**Month**

**p=0.105 **
**at Month 24**

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

**12%**

**19%**

**0%**

**16%**

**0**

**5**

**10**

**15**

**20**

**% (No.) of Patients**

**Placebo**

**Mito 12**

**12**

**24**

**12**

**24**

**Month**

**(n=7)**

**(n=5)**

**(n=4)**

**(n=0)**

**p=0.0236 **
**at Month 24**

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

**0.58**

**2.36**

**0.64**

**4.28**

**0**

**1**

**2**

**3**

**4**

**5**

**Mean Score Change**

**Placebo**

**Mito 12**

**12**

**24**

**12**

**24**

**Month**

**p=0.125 **
**at Month 24**

## 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

**Study 902****Design and Efficacy Results**

## 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

**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

**Corticosteroids in previous month**
**Immunosuppressive therapy in previous 3 months**
**Cardiac risk factors or major illness**
**Pregnancy or breast feeding**

## Study 902 - Design

**Triage**

**M -2**

**M -1**

**M 0**

**M 1**

**M 2**

**M 3**

**M 4**

**M 5**

**M 6**

**M 1**

**M 2**

**M 3**

**M 4**

**M 5**

**M 6**

**Randomized Treatment**

**methylprednisolone 1 g/month IV**

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

## Study 902 - Efficacy Evaluations

**Monthly MRI**
**MRI evaluators masked to study drug and outcome**
**Monthly clinical evaluations**
**Treating physicians not masked****to study drug**
**Evaluated EDSS, relapses, safety**

## 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

**Withdrew**
**after 1 dose**
**n=1**

**Withdrew****LoE**
**n=5**

**Withdrew**
**after 1 dose**
**n=1**

**Randomized**
**n=44**

**Mito + mP**
**n=22**

**Mito + mP ****completed study**
**n=21**

**mP ****completed study**
**n=16**

**mP**
**n=22**

## 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

**0**

**20**

**40**

**60**

**80**

**100**

**% of patients**

**-1**

**0**

**1**

**2**

**3**

**6**

**5**

**4**

**Month**

*****

**†**

**‡**

**§**

*** ****	****p=0.009**
**† ****	****p=0.030 **
**‡ ****	****p=0.033**
**§ ****	****p=0.001**

**86%**

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

**Number of new Gd+ Lesions**

**0**

**5**

**10**

**15**

**20**

**-1**

**0**

**1**

**2**

**3**

**6**

**5**

**4**

**Month**

**p=0.001****at Month 6**

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

**Mean EDSS Change**

**-2**

**-1**

**0**

**1**

**2**

**0**

**1**

**2**

**3**

**6**

**5**

**4**

**Month**

**p=0.013****at Month 6**

## 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

**	****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

**Mitoxantrone + mP vs mP alone**
**Decreases number of patients with new****Gd+ lesions  (86%)**
**Slows progression of neurologic impairment  (1.0 point EDSS -- 83%)**
**Decreases relapse rate  (77%)**

## Mitoxantrone Safety Data

## Mitoxantrone Safety Experience

## 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

**	****Placebo****	****Mito 5****	****Mito 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**

**% of Patients**

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

## Study 901 - Clinical Adverse Events in 10% 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**

**% of Patients**

## 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%

**	****	****	****	****	****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****	****	**

**Number of Patients**

**No congestive heart failure**

## 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

**No deaths**
**Pregnancy: 2 reported**
**1 placebo - terminated pregnancy**
**1 mitoxantrone 12 mg/m****2**** - normal child **

## Study 901 - Hematology Results  Normal*

**	****Placebo****	****Mito 5****	****Mito 12****	**** (n=64)****	****(n=64)****	****(n=60)**
**Hemoglobin****	****14****	****15****	****14**
**Platelets****	****3****	****5****	****6**
**WBC****	****5****	****15****	****20**

**Number of Patients**

*** 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*

**	****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**

**Number of Patients**

*** Any grade, all reversible.**

## 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*

**WBC ******** 2,000/μL****	****48**
**ANC ******** 1,000/μL ****	****86**
**Hemoglobin ******** 10 g/dL****	****0**
**Platelets ******** 100,000/μL****	****0**

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

*** Nadir leukopenia Week 1 or 2**

## 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

**Staff hired exclusively for data collection**
**Collection of specified safety and****efficacy 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

**Mitoxantrone 12 mg/m****2**** 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

**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. relapses****in 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)**

**32%**

**40%**

**18%**

**0**

**20**

**40**

**60**

**80**

**100**

**% (No.) of Patients**

**(n=144)**

**(n=181)**

**(n=80)**

**1-2**

**3-5**

**6-8**

******9**

**11%**

**(n=49)**

**No. of Doses**

## 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

**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

**	****	****	****	****Cycle****	****Mitoxantrone**
**	****	****	****	****of****	**** Cumulative****	****Type of Event****	****No.****	****Event****	****Dose (mg/m****2****)**
**	****Decreased LVEF****	****5****	****7-12****	****50-130**
**	****Arrhythmia****	****1****	****1****	****11**
**	****Mitral valve insuf.****	****1****	****4****	****41**
**	**

## Mitoxantrone Cardiac Effects in Cancer Patients*

**Mitoxantrone given every 3-4 weeks**
**Often with other chemotherapy/chest radiation**
**At cumulative dose of 140 mg/m****2**
**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

**Adverse events mild or moderate**
**Manageable and reversible**
**Dose up to 100 mg/m****2**** 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

**Well characterized adverse events **
**Monitoring**
**Management**
**Clear benefit in progressive MS**
**Benefits outweigh risks**
**Disease stage without satisfactory therapy**

## 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

**Serum chemistries (including LFT)**
**Before each course**
**Hemogram**
**Before each course**
**If fever develops at expected****leukocyte nadir **

## Cardiac Monitoring

**LVEF assessment**
**At baseline**
**At cumulative dose of 100 mg/m****2**
**Assess risk/benefit and monitor LVEF****before each course if:**
**Cumulative dose ******** 100 mg/m****2**
**LVEF decreases by ******** 15% from baseline**
**Discontinue therapy if:**
**LVEF **** 50% **
**Cumulative dose ******** 140 mg/m****2**

## Pregnancy

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

## 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

**Study 902 (mP vs Mitoxantrone + mP)**
**Slows progression of neurologic impairment  (EDSS - 83%)**
**Decreases relapse rate  (77%)**
**Decreases number of patients with new****Gd+ lesions  (86%)**
**Study 903**
**Therapy feasible in practice setting**

## Discussion

## 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

**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

**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

**EDSS assessment unmasked**
**Results robust**
**Significant difference between mitoxantrone and control**
**Consistency of EDSS results in the****2 randomized studies**

## 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 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

**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/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/m****2**
**Substantial safety information in Study 901, 902, 903, and oncology safety databases**

## Target Population

**Patients with progressive forms of MS excluding primary progressive MS**

## Mitoxantrone in Multiple Sclerosis:A Clinician’s Perspective

**Fred D. Lublin, M.D.**
**Professor of Neurology****MCP Hahnemann University**

## Clinical Courses of MS

**Increasing Disability**

**Time**

**Relapsing**
**remitting**

**Secondary ****progressive**

**Primary **
**progressive**

## Mechanisms of Worsening of MS

**Relapsing-remitting disease with incomplete recovery (step-wise worsening)**
**Gradual, progressive worsening independent of relapses**

## Mechanisms of Worsening of MS

## Slide 111

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

**Increasing Disability**

**Time**

**Relapsing**
**remitting**

## Conclusions

## 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

**To slow progression of neurologic disability and reduce relapse rate**
**Patients with progressive forms of MS excluding primary progressive MS**
**Dose 12 mg/m****2 ****every 3 months**
**Disease control for 2-3 years beneficial**
**Patients with limited therapeutic options**