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

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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  1. Peripheral & Central Nervous System DrugsAdvisory Committee January 28, 2000 Mitoxantrone for Multiple Sclerosis (Novantrone®) Immunex Corporation

  2. 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

  3. 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

  4. H H NCH2CH2NCH2CH2OH HO O 2 HCL O HO NCH2CH2NCH2CH2OH H H Mitoxantrone Mechanism of Action • Affects dividing and non-dividing cells via inhibition of DNA synthesis and repair • DNA intercalation • DNA topoisomerase II inhibition

  5. 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)

  6. Multiple Sclerosis • MS is a debilitating disease • Afflicts 350,000+ Americans • 140,000+ with secondary progressive MS • No currently approved treatment options

  7. Mitoxantronefor MS - Regulatory History • End of Phase III meeting 11/2/98 • Pre-NDA meeting 4/15/99 • NDA submitted 6/4/99 • Priority review status 7/26/99 • Orphan designation granted 8/13/99

  8. 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.”

  9. Presentation Agenda • IntroductionAnn Hayes, M.D. Senior Vice President Immunex Corporation • Efficacy & SafetyRichard Ghalie, M.D. Senior Director Immunex Corporation • Clinician’s Fred Lublin, M.D. Perspective Professor of Neurology MCP Hahnemann University

  10. Study Investigators • H. Peter Hartung, MD Chairman, Department of Neurology Graz University, Austria Chairman, Study 901 • Gilles Edan, MD Chairman, Department of Neurology CHU Rennes, France Chairman, Study 902 • Erich Mauch, MD Medical Director, Neurology Clinic Academic Hospital of Ulm University, Germany Chairman, Study 903

  11. Immunex Advisors • Hillel Panitch, MD Professor, Department of Neurology University of Maryland Baltimore, MD • Craig Smith, MD Clinical Professor of Neurology, Medicine and Ophthalmology University of Washington Seattle, WA • David Alberts, MD Professor of Medicine, Pharmacology and Public Health Associate Dean for Research University of Arizona Tucson, AZ

  12. Mitoxantrone in Multiple Sclerosis (MS) Efficacy and Safety Review

  13. 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

  14. Published Studies of Mitoxantrone in MS No. of Dose (mg/m2) Author Patients Schedule Gonsette (1990) 22 14 q 3 w Kappos (1990) 14 10 q 3 w Mauch (1992) 10 12 q 3 m Noseworthy (1993) 13 8 q 3 w Rugerro (1993) 14 8 q 3 w Millefiorini (1997) 27 8 q m x 12 vs. placebo Total 100 8-14 mg/m2 q 3w - 3m

  15. 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

  16. Study 901Design and Efficacy Results

  17. 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

  18. 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

  19. 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

  20. 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

  21. 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

  22. 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

  23. 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)

  24. 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%

  25. 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

  26. 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)

  27. 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

  28. Study 901 - Early Drug Discontinuation Number of Patients Placebo Mito 5 Mito 12Reason for discontinuation (n=64) (n=64) (n=60) Lack of efficacy 8 3 4 Patient refusal 6 3 2 Lost to follow-up 1 3 0 Adverse event 2 0 5 Other 0 1 1 Total discontinued 17 10 12 Completed 2 years 47 (73%) 54 (84%) 48 (80%)

  29. Placebo Mito 5 Mito 12 (n=64) (n=64) (n=60) No. females (%) 31 (48) 39 (61) 28 (47) Mean age (years) 40 40 40 Type of MS Remittent progressive (%) 45 58 47 Secondary progressive (%) 55 42 53 Study 901 - Baseline Demographics

  30. Study 901 - Baseline DemographicsDisease Status Placebo Mito 5 Mito 12Mean Values (n=64) (n=64) (n=60) Duration of MS (years) 10 9 10 No. relapses prior year 1.3 1.4 1.3  EDSS last 18 months 1.6 1.6 1.5 EDSS at entry 4.7 4.7 4.5

  31. Study 901 - Primary Efficacy Criterion p-value Placebo Mito 5 Mito 12 Mito 12 (n=64) (n=64) (n=60) vs Placebo Multivariate primary efficacy criterion 0.0001 EDSS change (mean) 0.23 -0.23 -0.13 0.0194 AI change (mean) 0.77 0.41 0.30 0.0306 No. treated relapses (adj.) 76.8 46.9 24.1 0.0002 Time to 1st treatedrelapse (median, months) 14.2 NR NR 0.0004 SNS change (mean) 0.77 -0.38 -1.07 0.0269 NR = Median not reached within 24 months

  32. 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

  33. 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

  34. 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

  35. 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

  36. 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

  37. Patients (%) p-value Placebo Mito 5 Mito 12 Mito 12 (n=64) (n=64) (n=60) vs Placebo EDSS 1.0 point increaseconfirmed 3 months later 22 14 8 0.036 EDSS 1.0 point increaseconfirmed 6 months later 19 9 7 0.045 Patients requiring a wheelchair 11 8 5 NS Patients without relapses 36 39 57 0.021 Overall rating good/very good 17 42 43 0.001 QOL improvement 21 46 41 0.007 Worsening depression scale 40 44 37 NS Hospitalization other than drug admin. 67 56 40 0.002 Study 901 - Secondary Efficacy Variables

  38. Placebo Mito 12 -0.05 0.05 Mito 5 Study 901 - Mean Change in EDSS Quarterly Months 3 to 24 0.25 0.15 Change in EDSS -0.15 -0.25 -0.35 3 6 9 12 15 18 21 24 Months

  39. 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

  40. Study 901 - Categorized 1.0 PointEDSS Change Number (%) of Patients Placebo Mito 5 Mito 12 Change (n=64) (n=64) (n=60) Worsened* 16 (25%) 10 (16%) 5 (8%) Stable 41 (64%) 36 (56%) 43 (72%) Improved 7 (11%) 18 (22%) 12 (20%) * p=0.013 for Mito 12 vs Placebo

  41. 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

  42. Study 901 - Annualized Relapse Rate p-valueRelapse Placebo Mito 5 Mito 12 Mito 12Rate (n=43) (n=53) (n=42) vs placebo Baseline 1.3 1.4 1.3 NS Year 1 1.2 0.7 0.4 < 0.0001 Year 2 0.9 0.5 0.3 0.0001 Years 1 + 2 1.0 0.6 0.4 0.0002

  43. 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

  44. 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

  45. 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

  46. 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

  47. 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

  48. 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

  49. 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

  50. 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

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