1. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-1 Mitoxantrone for Multiple Sclerosis (Novantrone ® ) Mitoxantrone for Multiple Sclerosis (Novantrone ® ) Immunex Corporation Peripheral & Central Nervous System Drugs Advisory Committee January 28, 2000

2. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-2 Mitoxantrone Approved Indications Adult acute myeloid leukemia (1987) Adult acute myeloid leukemia (1987) –12 mg/m 2 /day x 3 days every 4-6 weeks Symptomatic hormone-refractory prostate cancer (1996) Symptomatic hormone-refractory prostate cancer (1996) –12-14 mg/m 2 every 3 weeks

3. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-3 Mitoxantrone Use in Cancer Patients Since approval Since approval –Over 180,000 patients treated in U.S. –Over 400,000 patients treated worldwide Range of dose and schedule 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 Alone or in combination with other drugs Well characterized safety profile Well characterized safety profile

4. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-4 Mitoxantrone Mechanism of Action Affects dividing and non-dividing cells via inhibition of DNA synthesis and repair Affects dividing and non-dividing cells via inhibition of DNA synthesis and repair –DNA intercalation –DNA topoisomerase II inhibition HOO HO O 2 HCL NCH 2 CH 2 NCH 2 CH 2 OH HH NCH 2 CH 2 NCH 2 CH 2 OH

5. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-5 Proposed Mechanism of Action in MS Antiproliferative effects -- reduces Antiproliferative effects -- reduces –B-lymphocytes –T-lymphocytes –Macrophages Immunomodulatory effects Immunomodulatory effects –Decreases antigen presentation –Decreases cytokine production (IL-2, TNF , IFN  )

6. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-6 Multiple Sclerosis MS is a debilitating disease MS is a debilitating disease Afflicts 350,000+ Americans Afflicts 350,000+ Americans 140,000+ with secondary progressive MS 140,000+ with secondary progressive MS –No currently approved treatment options

7. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-7 Mitoxantrone for MS - Regulatory History End of Phase III meeting11/2/98 End of Phase III meeting11/2/98 Pre-NDA meeting4/15/99 Pre-NDA meeting4/15/99 NDA submitted6/4/99 NDA submitted6/4/99 Priority review status7/26/99 Priority review status7/26/99 Orphan designation granted8/13/99 Orphan designation granted8/13/99

8. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-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. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-9 Presentation Agenda Introduction Ann Hayes, M.D. Senior Vice President Immunex Corporation Introduction Ann Hayes, M.D. Senior Vice President Immunex Corporation Efficacy & Safety Richard Ghalie, M.D. Senior Director 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 Clinician’s Fred Lublin, M.D. Perspective Professor of Neurology MCP Hahnemann University

10. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-10 Study Investigators H. Peter Hartung, MDChairman, Department of Neurology Graz University, Austria Chairman, Study 901 H. Peter Hartung, MDChairman, 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 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 Gilles Edan, MD Chairman, Department of Neurology CHU Rennes, France Chairman, Study 902

11. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-11 Immunex Advisors Hillel Panitch, MDProfessor, Department of Neurology University of Maryland Baltimore, MD Hillel Panitch, MDProfessor, Department of Neurology University of Maryland Baltimore, MD David Alberts, MDProfessor of Medicine, Pharmacology and Public Health Associate Dean for Research University of Arizona Tucson, AZ David Alberts, MDProfessor of Medicine, Pharmacology and Public Health Associate Dean for Research University of Arizona Tucson, AZ Craig Smith, MDClinical Professor of Neurology, Medicine and Ophthalmology University of Washington Seattle, WA Craig Smith, MDClinical Professor of Neurology, Medicine and Ophthalmology University of Washington Seattle, WA

12. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-12 Mitoxantrone in Multiple Sclerosis (MS) Efficacy and Safety Review

13. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-13 Mitoxantrone in Multiple Sclerosis Data Presentation and Discussion Efficacy data from 2 randomized trials Efficacy data from 2 randomized trials Safety data Safety data –Two randomized trials (901-902) –One retrospective study (903) –12+ years post marketing experience Benefit and risk assessment Benefit and risk assessment Discussion of questions raised by Dr. Katz Discussion of questions raised by Dr. Katz

14. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-14 Published Studies of Mitoxantrone in MS Gonsette (1990) 2214 q 3 w Kappos (1990) 1410 q 3 w Mauch (1992) 1012 q 3 m Noseworthy (1993) 13 8 q 3 w Rugerro (1993) 14 8 q 3 w Millefiorini (1997)278 q m x 12 vs. placebo Total1008-14 mg/m 2 q 3w - 3m No. of Dose (mg/m 2 ) AuthorPatients Schedule

15. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-15 Studies in Mitoxantrone Filing in MS Number of Patients StudyDesignMitoControlTotal 901Phase III12764191 901Phase III12764191 902Phase II222244 902Phase II222244 903Retrospective454n/a454 903Retrospective454n/a454 60386689

16. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-16 Study 901 Design and Efficacy Results

17. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-17 Study 901 - MIMS Trial Phase III, randomized, placebo-controlled study Phase III, randomized, placebo-controlled study 17 centers in 4 European countries 17 centers in 4 European countries 194 patients 194 patients Chairs - Professors H-P. Hartung and R. Gonsette Chairs - Professors H-P. Hartung and R. Gonsette Study approved by BfArM/Germany Study approved by BfArM/Germany June 1993 - July 1997 June 1993 - July 1997 ECTRIMS - 1998, 1999 and AAN - 1999

18. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-18 Study 901 - Inclusion Criteria Age 18 to 55 Age 18 to 55 MS according to Poser’s criteria MS according to Poser’s criteria Secondary progressive or remitting progressive* MS Secondary progressive or remitting progressive* MS EDSS progression  1 point in preceding 18 months EDSS progression  1 point in preceding 18 months Baseline EDSS from 3 to 6 Baseline EDSS from 3 to 6 * Relapsing remitting MS with residual deficit after relapse

19. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-19 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 Normal1076530 Ambulation impaired

20. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-20 Study 901 - Exclusion Criteria Benign or primary progressive MS Benign or primary progressive MS Relapse or treatment with corticosteroids in preceding 8 weeks Relapse or treatment with corticosteroids in preceding 8 weeks Prior treatment with mitoxantrone Prior treatment with mitoxantrone Immunosuppressive therapy in preceding 9 months Immunosuppressive therapy in preceding 9 months Cardiac risk factors Cardiac risk factors Major medical illness Major medical illness

21. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-21 Study 901 - Design Course every 3 months x 24 months Course every 3 months x 24 months Follow-up at Month 36 Follow-up at Month 36 Placebo Mitoxantrone 5 mg/m 2 Mitoxantrone 12 mg/m 2 RANDOMIZE

22. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-22 Study 901 - Masking Study Drug Placebo (methylene blue) to mask patients Placebo (methylene blue) to mask patients Evaluators of neurologic disability 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 MRI evaluators masked to study drug and outcomes Treating physicians not masked to study drug Treating physicians not masked to study drug –Drug administration and patient management –Evaluation of adverse events –Assessment and treatment of relapses

23. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-23 Study 901 - Primary Efficacy Criterion Single multivariate test * of 5 variables: 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 Mitoxantrone 12 mg/m 2 vs placebo at  = 0.05 * Wei-Lachin procedure (1992)

24. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-24 Study 901 - Test of Individual Efficacy Variables If p  0.05 in multivariate test If p  0.05 in multivariate test Then test individual variables in pre-determined order 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 At  = 0.05 for each endpoint If p  0.05 for any variable, no further testing If p  0.05 for any variable, no further testing 60 patients per group, power = 90% 60 patients per group, power = 90%

25. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-25 Study 901 - Kurtzke Expanded Disability Status Scale (EDSS) 10-point scale with 0.5 point increments 10-point scale with 0.5 point increments 7 functional systems (pyramidal, cerebellar, brain stem, sensorial, optic, bladder/bowel, mental) and other 7 functional systems (pyramidal, cerebellar, brain stem, sensorial, optic, bladder/bowel, mental) and other EDSS  4.5 defined by functional scores EDSS  4.5 defined by functional scores EDSS  5.0 defined by ambulation deficits EDSS  5.0 defined by ambulation deficits

26. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-26 Study 901 - AI and SNS Scales Ambulation Index (AI) Ambulation Index (AI) –10-point scale with 1-point increments –Evaluates ambulation deficits –AI  3 = help required for ambulation Standardized Neurological Status (SNS) score 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. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-27 Study 901 - Disposition of Patients Randomized N=194 Placebon=65 Mito 12 n=63 Mito 5 n=66 Not treated n=1 n=1 Withdrew after 1 course n=1 Not treated n=1 Withdrew after 1 course n=2 n=64n=64n=60

28. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-28 Study 901 - Early Drug Discontinuation Number of Patients Placebo Mito 5Mito 12 Reason for discontinuation (n=64)(n=64)(n=60) Lack of efficacy 834 Patient refusal632 Lost to follow-up130 Adverse event205 Other011 Total discontinued171012 Completed 2 years47 (73%)54 (84%)48 (80%)

29. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-29 Study 901 - Baseline Demographics Placebo Mito 5Mito 12 (n=64)(n=64)(n=60) Placebo Mito 5Mito 12 (n=64)(n=64)(n=60) No. females (%) 31 (48)39 (61)28 (47) Mean age (years)404040 Type of MS Remittent progressive (%)455847 Secondary progressive (%)554253

30. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-30 Study 901 - Baseline Demographics Disease Status Placebo Mito 5Mito 12 Mean Values(n=64)(n=64)(n=60) Duration of MS (years)10910 No. relapses prior year1.31.41.3  EDSS last 18 months 1.61.61.5 EDSS at entry4.74.74.5

31. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-31 Study 901 - Primary Efficacy Criterion NR = Median not reached within 24 months p-value p-value Placebo Mito 5Mito 12Mito 12 (n=64)(n=64)(n=60)vs Placebo Multivariate primary efficacy criterion  0.0001 EDSS change (mean)0.23-0.23-0.130.0194 AI change (mean) 0.770.410.300.0306 No. treated relapses (adj.) 76.846.924.10.0002 Time to 1 st treated relapse (median, months) 14.2NRNR0.0004 SNS change (mean) 0.77-0.38-1.070.0269 SNS change (mean) 0.77-0.38-1.070.0269

32. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-32 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

33. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-33 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

34. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-34 Study 901 - Mean Change in SNS Score -1.5 -0.5 0.0 0.5 1.0 0.77 Placebo -0.38 Mito 5 -1.07 Mito 12 p=0.0269 † Change M24  Baseline † Mito 12 vs Placebo

35. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-35 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

36. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-36 Study 901 - Time to First Treated Relapse 0.00 0.25 0.50 0.75 1.00 p=0.0004 Mito 12 vs Placebo 03691215182124 Months Proportion Event-Free Placebo Mito 5 Mito 12

37. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-37 Study 901 - Secondary Efficacy Variables p-value p-value Placebo Mito 5Mito 12 Mito 12 (n=64)(n=64)(n=60)vs Placebo EDSS 1.0 point increase confirmed 3 months later221480.036 EDSS 1.0 point increase confirmed 6 months later 19970.045 Patients requiring a wheelchair1185NS Patients without relapses3639570.021 Overall rating good/very good1742430.001 QOL improvement2146410.007 Worsening depression scale404437NS Hospitalization other than drug admin.6756400.002 Patients (%)

38. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-38 Study 901 - Mean Change in EDSS Quarterly Months 3 to 24 Change in EDSS Months -0.350.050.25 -0.25 -0.15 0.15-0.053691215182124Placebo Mito 5 Mito 12

39. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-39 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

40. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-40 Study 901 - Categorized  1.0 Point EDSS Change Number (%) of Patients Number (%) of Patients PlaceboMito 5Mito 12 Change(n=64)(n=64)(n=60) Worsened*16 (25%)10 (16%)5 (8%) Stable41 (64%)36 (56%)43 (72%) Improved7 (11%)18 (22%)12 (20%) * p=0.013 for Mito 12 vs Placebo

41. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-41 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

42. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-42 Study 901 - Annualized Relapse Rate p-value Relapse PlaceboMito 5Mito 12Mito 12 Rate(n=43)(n=53)(n=42)vs placebo Baseline1.31.41.3NS Year 11.20.70.4 < 0.0001 Year 20.90.50.3 0.0001 Years 1 + 2 1.00.60.4 0.0002

43. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-43 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 0.460.040.10 SNS 3.28 1.51 0.19 AI 1.13 0.55 0.61 * Not masked Months 24 to 36

44. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-44 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

45. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-45 Study 901 - Time to First Treated Relapse - Month 0 to 36* Placebo Mito 5 Mito 12 0.0 0.2 0.4 0.6 0.8 1.0 Months Proportion Event-Free 061218243036 Discontinuation of study drug * Not masked Months 24 to 36

46. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-46 Study 901 - Clinical Efficacy Conclusions Mitoxantrone 12 mg/m 2 vs placebo: 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 No disease rebound 1 year after treatment discontinuation Dose response effect Dose response effect

47. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-47 Study 901 - MRI Subgroup Evaluation T1-w Gd-enhanced and T2-w scans T1-w Gd-enhanced and T2-w scans Scans performed at baseline, end of Years 1 and 2 Scans performed at baseline, end of Years 1 and 2 110 patients in specified sites 110 patients in specified sites MRI review: MRI review: –Centrally at the end of the study –Evaluators masked to study drug and clinical outcomes

48. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-48 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) 12240 12240 Month p=0.105 at Month 24

49. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-49 Study 901 - Patients with New Gd-Enhancing Lesions 12% 19% 0% 16% 0 5 10 15 20 % (No.) of Patients Placebo Mito 12 1224 1224 Month (n=7) (n=5) (n=4) (n=0) p=0.0236 at Month 24

50. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-50 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 1224 1224 Month p=0.125 at Month 24

51. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-51 Study 901 - MRI Efficacy Conclusions Mitoxantrone Mitoxantrone –Decreased Gd-enhancing lesions –Slowed progression of T2-w lesion load Indicates a reduction of inflammation in CNS Indicates a reduction of inflammation in CNS Support clinical findings of study Support clinical findings of study

52. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-52 Study 902 Design and Efficacy Results

53. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-53 Study 902 - Phase II Trial in Active MS Randomized, corticosteroid-controlled trial Randomized, corticosteroid-controlled trial 5 academic centers in France 5 academic centers in France 44 patients 44 patients Chair - Professor G. Edan Chair - Professor G. Edan April 1992 - March 1995 April 1992 - March 1995 Journal of Neurology, Neurosurgery and Psychiatry 1997

54. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-54 Study 902 - Inclusion Criteria Age 18 to 45 Age 18 to 45 Disease history of less than 10 years Disease history of less than 10 years Highly active disease Highly active disease –EDSS progression  2 points –Or  2 relapses –In preceding 12 months Baseline EDSS  6.0 Baseline EDSS  6.0

55. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-55 Study 902 - Exclusion Criteria Corticosteroids in previous month Corticosteroids in previous month Immunosuppressive therapy in previous 3 months Immunosuppressive therapy in previous 3 months Cardiac risk factors or major illness Cardiac risk factors or major illness Pregnancy or breast feeding Pregnancy or breast feeding

56. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-56 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

57. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-57 Study 902 - Efficacy Evaluations Monthly MRI Monthly MRI –MRI evaluators masked to study drug and outcome Monthly clinical evaluations Monthly clinical evaluations –Treating physicians not masked to study drug –Evaluated EDSS, relapses, safety

58. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-58 Study 902 - Study Endpoints Primary MRI endpoint* Primary MRI endpoint* –Number of patients with new Gd+ lesions monthly x 6 Secondary MRI endpoint Secondary MRI endpoint –Number of new Gd+ lesions monthly x 6 Secondary clinical endpoints Secondary clinical endpoints –EDSS –Relapse Main comparisons at Month 6 Main comparisons at Month 6 * Miller et al, 1991

59. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-59 Study 902 - Patient Disposition Withdrew after 1 dose n=1 Withdrew LoE n=5 Withdrew after 1 dose n=1 Randomizedn=44 Mito + mP n=22 Mito + mP completed study n=21 mP completed study n=16 mPn=22

60. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-60 Study 902 - Baseline Demographics mP Mito + mP (n=21)(n=21) mP Mito + mP (n=21)(n=21) No. females (%)11 (52)15 (71) Mean age (years) 3231 Mean duration of MS (years) 5.76.9 No. RRMS/SPMS15/617/4 Mean relapses in preceding 12 months 2.93.1 Mean EDSS4.74.4 RRMS = Relapsing-remitting MS based on  2 relapses. SPMS = Secondary progressive MS based on  2.0 points EDSS increase.

61. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-61 Study 902 - Patients With New Gd-Enhancing Lesions mP Mito + mP 0 20 40 60 80 100 % of patients 0123654 Month * † ‡ § * p=0.009 † p=0.030 ‡ p=0.033 § p=0.001 86%

62. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-62 Study 902 - Mean (±SEM) Number of New Gd-Enhancing Lesions Number of new Gd+ Lesions 0 5 10 15 200123654 Month p=0.001 at Month 6 mP Mito + mP

63. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-63 Study 902 - Mean (±SEM) EDSS Change Mean EDSS Change -2 0 1 2 0123654 Month p=0.013 at Month 6 mP Mito + mP

64. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-64 Study 902 - Categorized  1.0 Point EDSS Change mPMito + mP Change(n=21)(n=21)p-value Worsened 6 (29%)1 (5%)0.038 Stable12 (57%)8 (38%)0.217 Improved3 (14%)12 (57%)0.004

65. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-65 Study 902 - Relapse Assessment mPMito + mP (n=21)(n=21)p-value (n=21)(n=21)p-value Baseline annualized2.93.1NS relapse rate relapse rate On study annualized 3.00.70.003 relapse rate Patients free of 7 (33%)14 (67%)0.031 relapses on study

66. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-66 Study 902 - Efficacy Conclusions Mitoxantrone + mP vs mP alone 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%)

67. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-67 Mitoxantrone Safety Data

68. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-68 Mitoxantrone Safety Experience StudyDescriptionPatients 901Phase III randomized, controlled127 902Phase II randomized, controlled22 90310 year retrospective study454 Total603

69. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-69 Study 901 - Discontinuation Due to AE GroupMonthReason for Withdrawal Mito 12 * 18Nausea and emesis (n=5)3Depression 12  LVEF  10% from baseline 12Urinary tract infection 18Renal failure after retention Mito 5 0— Placebo15Myocardial infarction (n=2)18Liver function abnormalities * One additional patient withdrew after Cycle 1 due to MS progression, bilirubin = 3.3, and patient refusal.

70. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-70 Study 901 - Clinical Adverse Events More Frequent (p  0.05) in Either Mitoxantrone Group PlaceboMito 5Mito 12 (n=64)(n=65)(n=62) Nausea205576 Alopecia313861 UTI132932 Menstrual disorder265161 Amenorrhea32863 % of Patients All AE were grade 1 or 2 except 5% of nausea in Mito 12.

71. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-71 Study 901 - Clinical Adverse Events in  10% of Patients PlaceboMito 5Mito 12 Adverse Event(n=64)(n=65)(n=62) Nausea205576 Alopecia313861 Urinary tract infection132932 Upper respiratory tract infection525153 Stomatitis81519 Arrhythmia8618 Diarrhea112516 Urine abnormal6511 ECG abnormal3511 Constipation61410 Rhinitis14118 Menstrual disorder265161 Amenorrhea32863 % of Patients

72. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-72 Study 901 - Cardiac Monitoring Clinical evaluation before each course Clinical evaluation before each course ECG before each course ECG before each course Echocardiogram at baseline, Years 1, 2, 3 Echocardiogram at baseline, Years 1, 2, 3

73. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-73 Study 901 - Number of Patients with LVEF  50% PlaceboMito 5Mito 12 Year 10/641/642/59 Year 21/471/541/52 Year 30/351/441/36 Number of Patients No congestive heart failure

74. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-74 Study 901 - LVEF Values  50% Month 24 to 36 Number of Patients Mito 5Mito 12 LVEF Change (n=43)(n=36) Worsened from 11  50% to  50%  50% to  50% Improved from 10  50% to  50% No congestive heart failure

75. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-75 Study 901 - Additional Safety Information No deaths No deaths Pregnancy: 2 reported Pregnancy: 2 reported –1 placebo - terminated pregnancy –1 mitoxantrone 12 mg/m 2 - normal child

76. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-76 Study 901 - Hematology Results  Normal* PlaceboMito 5Mito 12 (n=64)(n=64)(n=60) Hemoglobin141514 Platelets356 WBC51520 Number of Patients * Any grade, all reversible. No transfusions. No difference in incidence of severe infections and hospitalizations for infection in the 3 groups.

77. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-77 Study 901 - Serum Chemistries  Normal* PlaceboMito 5Mito 12 (n=64)(n=64)(n=60) Creatinine767 Bilirubin151310 GGT201919 SGOT111920 Alkaline phos.885 Number of Patients * Any grade, all reversible.

78. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-78 Study 902 - Adverse Events Profile similar to Study 901 Profile similar to Study 901 3 adverse events considered severe (amenorrhea, depression/anorexia, contact lens intolerance) 3 adverse events considered severe (amenorrhea, depression/anorexia, contact lens intolerance) No deaths on study No deaths on study No cardiac toxicity (echocardiogram at baseline and M6) No cardiac toxicity (echocardiogram at baseline and M6)

79. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-79 Study 902 - Grade 3-4 Hematologic Toxicity of Mito + mP* WBC  2,000/µL48 ANC  1,000/µL 86 Hemoglobin  10 g/dL0 Platelets  100,000/µL0 % of Patients (n=21) * Nadir leukopenia Week 1 or 2

80. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-80 Study 903 - Long Term Safety Database Academic Clinic of Ulm University, Germany Academic Clinic of Ulm University, Germany Professor Erich Mauch Professor Erich Mauch Retrospective analysis Retrospective analysis Mitoxantrone given between 11/88 and 9/98 Mitoxantrone given between 11/88 and 9/98 454 patients 454 patients All patients included All patients included ECTRIM - 1999

81. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-81 Study 903 - Data Collection and Quality Assurance Staff hired exclusively for data collection Staff hired exclusively for data collection Collection of specified safety and efficacy data Collection of specified safety and efficacy data Attempt to obtain most recent follow-up Attempt to obtain most recent follow-up Information on treatment off site not collected Information on treatment off site not collected All CRFs reviewed by Dr. Mauch for accuracy All CRFs reviewed by Dr. Mauch for accuracy

82. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-82 Study 903 - Treatment Guidelines Mitoxantrone 12 mg/m 2 every 3 months Mitoxantrone 12 mg/m 2 every 3 months Dose adjustment or interval change as needed Dose adjustment or interval change as needed Treatment discontinued if: Treatment discontinued if: –Not tolerated –Good disease response –Attempt to become pregnant

83. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-83 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)

84. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-84 Study 903 - Mitoxantrone Dosing (N=454) 32% 40% 18% 0 20 40 60 80 100 % (No.) of Patients (n=144) (n=181) (n=80) 1-23-56-8 9999 11% (n=49) No. of Doses

85. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-85 Study 903 - Mortality (N=454) Number of Cause of Death Patients Infections9 Respiratory failure5 Heart failure 2 Cachexia1 Unknown - late deaths3 Total20 (4%)

86. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-86 Study 903 - Pregnancies Pregnancies Pregnancies –4 during mitoxantrone treatment –5 after discontinuing treatment Births Births –6 normal –1 pregnant at data collection –2 outcomes not available

87. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-87 Study 903 - Cardiac Abnormalities CycleMitoxantrone of Cumulative Type of EventNo.EventDose (mg/m 2 ) Decreased LVEF57-1250-130 Arrhythmia1111 Mitral valve insuf.1441

88. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-88 Mitoxantrone Cardiac Effects in Cancer Patients* Mitoxantrone given every 3-4 weeks Mitoxantrone given every 3-4 weeks Often with other chemotherapy/chest radiation Often with other chemotherapy/chest radiation At cumulative dose of 140 mg/m 2 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 Occur during or within a year of completing mitoxantrone therapy * Published literature and Immunex databases

89. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-89 Mitoxantrone Safety Conclusions Adverse events mild or moderate Adverse events mild or moderate Manageable and reversible Manageable and reversible Dose up to 100 mg/m 2 in MS trials not associated with congestive heart failure Dose up to 100 mg/m 2 in MS trials not associated with congestive heart failure Myelosuppression Myelosuppression –Reversible within 1 - 3 weeks –Not associated with severe infection No secondary leukemia or myelodysplasia No secondary leukemia or myelodysplasia

90. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-90 Risk & Benefit Assessment Well characterized adverse events Well characterized adverse events –Monitoring –Management Clear benefit in progressive MS Clear benefit in progressive MS Benefits outweigh risks Benefits outweigh risks –Disease stage without satisfactory therapy

91. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-91 Acute Adverse Events Mild to moderate intensity Mild to moderate intensity Nausea and emesis: transient, manageable Nausea and emesis: transient, manageable Alopecia mild, reversible Alopecia mild, reversible Leukopenia Leukopenia –Grade 3-4 in  50% of patients –Between day 7-14 –Reversible by day 21 –Risk of neutropenic fever low

92. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-92 Laboratory Monitoring Serum chemistries (including LFT) Serum chemistries (including LFT) –Before each course Hemogram Hemogram –Before each course –If fever develops at expected leukocyte nadir

93. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-93 Cardiac Monitoring LVEF assessment LVEF assessment –At baseline –At cumulative dose of 100 mg/m 2 Assess risk/benefit and monitor LVEF before each course if: 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: Discontinue therapy if: –LVEF  50% –Cumulative dose  140 mg/m 2

94. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-94 Pregnancy Mitoxantrone should not be used in pregnant women or in women attempting to become pregnant (already in label) Mitoxantrone should not be used in pregnant women or in women attempting to become pregnant (already in label)

95. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-95 Benefit of Mitoxantrone - Study 901 Slows progression of neurologic impairment Slows progression of neurologic impairment –Decreases 1.0 EDSS progression by 64% Reduces relapses Reduces relapses –Decreases treated relapses by 69% Lessens CNS lesions Lessens CNS lesions –Substantial decrease in number of patients with Gd-enhanced lesions –Slows progression of T2w lesions

96. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-96 Benefit of Mitoxantrone - Supportive Studies Study 902 (mP vs Mitoxantrone + mP) 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 Study 903 –Therapy feasible in practice setting

97. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-97 Discussion

98. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-98 Adequacy of Controlled Study 901 Well designed, randomized, placebo- controlled Well designed, randomized, placebo- controlled Prospectively defined entry criteria, endpoints, number of patients, and statistical analyses Prospectively defined entry criteria, endpoints, number of patients, and statistical analyses Effect on disability and relapse using established scales Effect on disability and relapse using established scales MRI prospectively limited to subset MRI prospectively limited to subset

99. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-99 Adequacy of Controlled Study 902 Well designed, randomized, controlled Well designed, randomized, controlled Prospectively defined entry criteria, endpoints Prospectively defined entry criteria, endpoints Design typical of MRI-based trial Design typical of MRI-based trial Effect on disability and relapse using established scales Effect on disability and relapse using established scales

100. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-100 Mitoxantrone Slows Progression of Neurologic Disability - Study 901 Used 3 complementary disability scales Used 3 complementary disability scales All 3 primary disability endpoints met All 3 primary disability endpoints met Secondary disability endpoints met Secondary disability endpoints met No rebound one year after stopping therapy No rebound one year after stopping therapy

101. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-101 Mitoxantrone Slows Progression of Neurologic Disability - Study 902 EDSS assessment unmasked EDSS assessment unmasked Results robust Results robust –Significant difference between mitoxantrone and control –Consistency of EDSS results in the 2 randomized studies

102. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-102 Mitoxantrone Decreases Relapse Relapse definition/severity Relapse definition/severity –prospectively defined in both studies Consistency of results in the 2 studies Consistency of results in the 2 studies Highly significant vs control group Highly significant vs control group Consistency in all relapse evaluations Consistency in all relapse evaluations

103. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-103 MRI Results - Study 901 MRI evaluations MRI evaluations –In subset of patients –No stratification by baseline MRI –Study not sized for MRI endpoints Decreased Gd+ lesions Decreased Gd+ lesions –Consistent with clinical results –Suggests biologic effect

104. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-104 MRI Results - Study 902 Design typical of MRI-based trial Design typical of MRI-based trial Nine monthly scans per patient Nine monthly scans per patient MRI findings MRI findings –Highly significant –Consistent with clinical results –Indicate mitoxantrone biologic effect Consistent MRI results in both studies Consistent MRI results in both studies

105. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-105 Dose - 12 mg/m 2 Every 3 Months Investigational dose in Study 901 Investigational dose in Study 901 Significantly better than placebo for all primary and most secondary variables Significantly better than placebo for all primary and most secondary variables Dose of 20 mg (Study 902)  12 mg/m 2 Dose of 20 mg (Study 902)  12 mg/m 2 Substantial safety information in Study 901, 902, 903, and oncology safety databases Substantial safety information in Study 901, 902, 903, and oncology safety databases

106. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-106 Target Population Patients with progressive forms of MS excluding primary progressive MS Patients with progressive forms of MS excluding primary progressive MS

107. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-107 Mitoxantrone in Multiple Sclerosis: A Clinician’s Perspective Fred D. Lublin, M.D. Professor of Neurology MCP Hahnemann University

108. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-108 Clinical Courses of MS Increasing Disability Time Relapsingremitting Secondary progressive PrimaryprogressiveProgressiverelapsing

109. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-109 Mechanisms of Worsening of MS Relapsing-remitting disease with incomplete recovery (step-wise worsening) Relapsing-remitting disease with incomplete recovery (step-wise worsening) Gradual, progressive worsening independent of relapses Gradual, progressive worsening independent of relapses

110. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-110 Mechanisms of Worsening of MS

111. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-111

112. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-112 Clinical Courses of MS - Worsening Forms of Relapsing or Progressive Disease Increasing Disability Time RelapsingremittingProgressiverelapsing Secondary progressive

113. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-113 Conclusions

114. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-114 Effectiveness of Mitoxantrone in MS Study 901 Study 901 –Primary endpoint - clinical –MRI data consistent with clinical findings Study 902 Study 902 –Primary endpoint - MRI –Clinical data consistent with MRI findings

115. Novantrone Main Presentation Version 7.0 - 10/3/2015 M-115 Proposed Use of Mitoxantrone in MS To slow progression of neurologic disability and reduce relapse rate To slow progression of neurologic disability and reduce relapse rate Patients with progressive forms of MS excluding primary progressive MS Patients with progressive forms of MS excluding primary progressive MS Dose 12 mg/m 2 every 3 months Dose 12 mg/m 2 every 3 months Disease control for 2-3 years beneficial Disease control for 2-3 years beneficial Patients with limited therapeutic options Patients with limited therapeutic options