Ipilimumab ASCO Data Review and Discussion Webcast Monday, June 2, 2008
Slide 2 Forward Looking Statements Except for historical information, the matters contained in this slide presentation may constitute forward-looking statements that involve risks and uncertainties, including uncertainties related to product development and clinical trials that could cause actual results to differ materially from any future results, performance or achievements expressed or implied by such statements. These risks and uncertainties include whether the actual results in the clinical studies described will differ materially from future results, whether development of ipilimumab and other products will be successful, whether the clinical studies described will support the filing of a BLA with the FDA, or whether, if a BLA is filed with FDA, it will be filed in the timeframe developed by the parties or will receive regulatory approval, as well as risks detailed from time to time in Medarex s public disclosure filings with the U.S. Securities and Exchange Commission (SEC). All forward-looking statements included in this slide presentation are based on information available to us as of June 2, 2008. We do not assume any obligation to update any information contained in these materials. Our actual results may differ materially from the results discussed in the forward-looking statements.
Slide 3 Agenda Welcome Howard H. Pien President and Chief Executive Officer, Medarex, Inc. Ipilimumab Data in Melanoma Jedd D. Wolchok, M.D., Ph.D. Memorial Sloan-Kettering Cancer Center Ipilimumab Phase 3 Updates in Melanoma and Prostate Cancer Geoffrey M. Nichol, MBChB Senior Vice President, Product Development, Medarex, Inc. Medarex Milestones Christian S. Schade Senior Vice President and Chief Financial Officer, Medarex, Inc. Q&A Session
Slide 4 Ipilimumab Data in Melanoma Jedd D. Wolchok, M.D., Ph.D. Memorial Sloan-Kettering Cancer Center
Slide 5 Summary Prolonged overall survival and one-year survival rates favorable compared to medical literature New response patterns were observed that were associated with survival mwho response criteria may not adequately capture clinical activity of ipilimumab New lesions may not always indicate progression or treatment failure Responses may occur after initial progression 10mg/kg is optimal ipilimumab dosing regimen with acceptable benefit : risk ratio Immune-related adverse events generally manageable and reversible using established treatment guidelines Treatment guidelines effective in decreasing incidence of serious adverse events complications (e.g. gastrointestinal)
Slide 6 Ipilimumab Phase 2 Study Characteristics Study CA184008 N=155 Single arm; 10 mg/kg Progression on or after prior approved or frequently used therapy Study CA184022 N=217 3-arm: 10 mg/kg, 3 mg/kg and 0.3 mg/kg Progression or intolerance to any prior therapy Study CA184007 N=115 10 mg/kg + placebo vs. 10 mg/kg + prophylactic budesonide Untreated or progression on or after any prior therapy
Slide 7 Main Eligibility Criteria Criteria 008 022 007 Stage III (unresectable) / Stage IV Yes Yes Yes Measurable Disease Yes Yes Yes Untreated / Treatment Naïve No No Yes Previously Treated Yes 1 Yes 2 Yes 3 ECOG Status 0 or 1 Yes Yes Yes Brain metastases No No Yes 1 Progressed on prior regimen containing: IL-2, DTIC, temozolomide, fotemustine, paclitaxel, carboplatin 2 Progressive Disease; no response in 3 months.; intolerance after any therapy 3 Untreated or Progressive Disease; intolerance after any therapy
Patient Demographics Study 008 Study 022 Study 007 Dosing regimen 10 mg/kg 10 mg/kg 3 mg/kg 0.3 mg/kg Data also referenced in 2008 ASCO Abstracts #3008 Hodi, #3020 Wolchok and #3022 Berman. Slide 8 10 mg/kg + placebo 10 mg/kg + prophylactic budesonide Patients treated 155 72 72 73 57 58 Age, median 59.0 56.5 59.0 59.0 61.0 58.0 Gender Male, n (%) Female, n (%) M-stage at study entry, n (%) M0 M1a (soft tissue) M1b (lung) M1c (all distant visceral or elevated LDH) 9 (5.8) 22 (14.2) 38 (24.5) 86 (55.5) 44 (61.1) 28 (38.9) 3 (4.2) 17 (23.6) 15 (20.8) 37 (51.4) 4 (5.6) 11 (15.3) 21 (29.2) 36 (50.0) 5 (6.8) 10 (13.7) 13 (17.8) 45 (61.6) 1 (1.8) 9 (15.8) 18 (31.6) 29 (50.9) 1 (1.7) 11 (19.0) 18 )31.0) 28 (48.3) Baseline LDH > Upper Limit of Normal 77 (49.7) 39 (54.2) 32 (44.4) 35 (47.9) Not provided Not provided Brain metastases, n (%) Not eligible Not eligible Not eligible Not eligible 5 (8.6) 7 (12.3) ECOG performance status, n (%) 0 1 2 Prior systemic therapy, n (%) Adjuvant Metastatic disease Neo-adjuvant Any prior systemic therapy, n (%) 0 1 2 3 4 5 80 (51.6) 75 (48.4) 95 (61.3) 60 (38.7) 57 (36.8) 153 (98.7) 2 (1.3) 61 (39.4) 39 (25.2) 31 (20.0) 16 (10.3) 8 (5.2) 41 (56.9) 31 (43.1) 0 27 (37.5) 70 (97.2) 0 48 (66.7) 24 (33.3) 4 (61.1) 28 (38.9) 0 24 (33.3) 71 (98.6) 1 (1.4) 52 (71.2) 21 (28.8) 46 (63.0) 26 (35.6) 1 (1.4) 32 (43.8) 72 (98.6) 0 72 (100.0) 72 (100.0) 73 (100.0) 38 (66.7) 19 (33.3) 40 (69.0) 17 (29.3) 1 (1.7) 26 (45.6) 25 (43.9) 0 16 (28.1) 18 (31.6) 14 (24.6) 7 (12.3) 0 2 (3.5) 43 (74.1) 15 (25.9) 42 (73.7) 15 (26.3) 0 20 (34.5) 38 (65.5) 1 (1.7) 8 (13.8) 22 (37.9) 13 (224) 12 (20.7) 2 (3.4) 1 (1.7) 2008 ASCO Abstracts #9021 O Day #9025 Hamid #9010 Weber, #9055 Thompson
Slide 9 Historical Survival Data in Previously Treated and Treatment Naïve Melanoma Patients Study Study Summary Median Overall Survival (95%CI) Survival rate at 1 year (95%CI) Korn EL, et al. JCO February, 2008 N=2100 Meta-analysis of 42 Phase 2 trials Stage IV melanoma 6.2 months (5.9, 6.5) 25.5% (23.6, 27.4) Chapman PB, et al. JCO September, 1999 * N=240 Phase 3: Dartmouth vs. DTIC Stage IV melanoma 7.0 months (6.1, 8.0) 25.0% Middleton MR, et al. JCO January, 2000 * N=305 Phase 3: temozolomide vs. DTIC Stage IV melanoma 6.4-7.7 months ~30% (per KM plot) Bedikian AY, et al. JCO October, 2006 * (Genasense study) N=771 Phase 3: DTIC +/- bcl-2 Advanced melanoma 7.8-9.0 months 9.7-11.4 months Normal LDH 4.6-4.7 months Elevated LDH ~30-35% (per KM plot) Agarawala SS, et al. JCO June, 2007 Supplement (Sorafenib PRISM study) N=270 Phase 3: carboplatin +/- sorafenib Advanced melanoma 10.5 months * Treatment naïve melanoma patients
Slide 10 Ipilimumab Survival Data Compares Favorably to Historical Data Study 008 (N=155) Study 022* (N=217) Study 007** (N=115) Dosing Regimen 10 mg/kg 10 mg/kg (n=72) 3 mg/kg (n = 72) 0.3 mg/kg (n =73) 10 mg/kg + placebo ( n=57) 10 mg/kg + prophylactic budesonide (n =58) Median Overall Survival in months (95%CI) 10.2 (7.3, ) 14.6 (6.9, ) 8.6 (6.9, 12.3) 8.6 (7.7, 14.5) Not Reached (11.5, ) Not Reached (6.8, ) % Survival Rate at 1 year (95%CI) 46.7 (38.6, 55.6) 53.4 (41.2, 63.7) 38.2 (25.3, 50.9) 40.4 (27.1, 53.8) 59.1 (45.4, 72.2) 58.8 (43.6, 70.3) Historical Median Overall Survival 6 to 9 months Historical % Survival Rate at 1 year 25% to 35% * Subjects with progressive disease at any time were eligible for re-induction with ipilimumab at 10mg/kg. ** Includes subjects with and without prior systemic therapy. Source: 2008 ASCO Abstracts #9021 O Day, #9025 Hamid, #9010 Weber, #9055 Thompson. Source for Historical Data: Chapman PB, et al. JCO September, 1999. Middleton MR, et al. JCO January, 2000. Bedikian AY, et al. JCO October, 2006. Korn EL, et al. JCO February, 2008.
Study 008: Overall Survival 1.0 0.8 10.2 months Median Overall Survival 46.7% 1-Year Survival Rate Proportion Alive 0.6 0.4 (Median follow-up: 9.5 months) 0.2 10 mg/kg ipilimumab Censored Data 0 0 2 4 6 8 10 12 14 16 18 20 Months Source: 2008 ASCO Abstract #9021 O Day. Slide 11
Study 022: Overall Survival 10mg/kg Cohort 14.6 months Median Overall Survival 53.4% 1-Year Survival Rate Proportion Alive (Median follow-up: 8.9 months) 10 mg/kg Censored Data 3 mg/kg Censored Data 0.3 mg/kg Censored Data Months Source: 2008 ASCO Abstract #9025 Hamid. Slide 12
Study 007: Median Overall Survival Not Reached 1.0 0.8 Ipilimumab + Placebo 59.1% 1-Year Survival Rate Proportion Alive 0.6 0.4 0.2 (Median follow-up: 10.9 months) Ipi + Placebo Censored Data Ipi + Prophylactic Budesonide Censored Data Ipilimumab + Prophylactic Budesonide 58.8% 1-Year Survival Rate 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Months Source: 2008 ASCO Abstracts #9010 Weber and #9055 Thompson. Slide 13
Study 007: 1-Year Survival Rates Ipilimumab + Placebo Group (N=57) 1-Year Survival Rate (%) Ipilimumab + Prophylactic Budesonide Group (N=58) 1-Year Survival Rate (%) Treatment Naïve (n=32) 67.2% Prior Treatment (n=25) 48.8% Treatment Naïve (n=21) 71.1% Prior Treatment (n=37) 51.4% 1.0 1.0 0.8 0.8 Proportion Alive 0.6 0.4 0.2 0 Prior systemic therapy Censored Data No prior systemic therapy Censored Data 0 2 4 6 8 10 12 14 16 18 20 22 Months Proportion Alive 0.6 0.4 0.2 0 Prior systemic therapy Censored Data No prior systemic therapy Censored Data 0 2 4 6 8 10 12 14 16 18 20 22 24 Months Source: 2008 ASCO Abstracts #9010 Weber and #9055 Thompson. Slide 14
Long-Term Second-line Survival Data with 30% Patients Alive Over 2 Years* Study MDX010-15: Ipilimumab 10mg/kg Induction Regimen Percent Overall Survival 10mg/kg Ipilimumab Cohort mos ~13.4 months 7 patients still alive 2.0+ to 2.4+ years (1CR, 1PR, 3SD, 2PD) * Data from 10mg/kg cohort (n=23) from MDX-010-15 protocol. Source: 2008 ASCO Abstract #3018 Urba. Slide 15 0 5 10 15 20 25 30 35 40 Months
Slide 16 Ipilimumab 1 to 4-Year Survival Rate Benchmark Data Study Disease Setting 1 year 2 years 3 years 4 years MDX010-08 (3 mg/kg + DTIC) (n=35) 1 st line only ~55% ~30% ~25% 10-15% MDX010-15 (10 mg/kg) (n=24) CA184-008 (10 mg/kg) (n=155) CA184-022 (10 mg/kg) (n=70) CA184-007 (10 mg/kg) (n=57) 1 st and 2 nd line pooled 2 nd line only 2 nd line only 1 st and 2 nd line pooled ~60% 46.7% 53.4% ~35% NA NA NA NA NA NA NA NA 59.1% NA NA NA Historical DTIC (Genasense study) (n=305) 1st line only 25-30% 10-15% NA NA Source for Ipilimumab Data: 2008 ASCO Abstracts #3018 Urba, #9022 Hersh, #9021 O Day, #9025 Hamid, #9010 Weber and #9055 Thompson. Source for Historical DTIC Data: Bedikian AY, et al. JCO October, 2006.
Ipilimumab Disease Control and Response Data Per mwho Criteria at Week 24 Study 008 (N=155) Study 022* (N=217) Study 007** (N=115) Dosing Regimen 10 mg/kg 10 mg/kg (n=72) 3 mg/kg (n = 72) 0.3 mg/kg (n =73) 10 mg/kg + placebo ( n=57) 10 mg/kg + prophylactic budesonide (n =58) Median Overall Survival in months (95%CI) 10.2 (7.3, ) 14.6 (6.9, ) 8.6 (6.9, 12.3) 8.6 (7.7, 14.5) Not Reached (11.5, ) Not Reached (6.8, ) % Disease Control Rate (CR+PR+SD) (95%CI) 27.1 (20.3, 34.8) 29.2 (19.0, 41.1) 26.4 (16.7, 38.1) 13.7 (6.8, 23.8) 35.1 (22.9, 48.9) 31.0 (19.5, 44.5) % BORR (mwho) (95%CI) 5.8 (2.7, 10.7) 11.1 (4.9, 20.7) 4.2 (0.9, 11.7) 0 (0.0, 4.9) 15.8 (7.5,27.9) 12.1 (5.0,23.3) * Subjects with progressive disease at any time were eligible for re-induction with ipilimumab at 10mg/kg. ** Includes subjects with and without prior systemic therapy. CR=Complete Response, PR=Partial Response, SD=Stable Disease Source: 2008 ASCO Abstracts #9021 O Day, #9025 Hamid, #9010 Weber and #9055 Thompson. Slide 17
Immunotherapy: Evolution of Anti-Cancer Effect ipilimumab ipilimumab ipilimumab ipilimumab Ipilimumab Exposure T-cell response beyond Week 12 has not been characterized T-cell Activation Total tumor volume * 25% 50% 100% SD PR CR Immune-cell activation and proliferation begins early Measurable clinical effect occurs at variable time points PD Patterns of Response Baseline SD PR CR CR = Complete Response, PR = Partial Response, SD = Stable Disease, PD = Progressive Disease * Tumor volume can include immune-cell infiltrates and tumor cells Slide 18 Source: 2008 ASCO Abstract #3008 Hodi.
Unique Patterns of Response Observed with Ipilimumab Therapy Ipilimumab therapy unlike conventional chemotherapy New response patterns observed associated with survival Response in baseline lesions Stable disease with slow, steady decline in total tumor burden Response after initial increase in total tumor burden Response in index lesions plus new lesions after appearance of new lesions mwho response criteria may not adequately capture clinical benefit of ipilimumab New lesions may not always indicate progression or treatment failure Source: 2008 ASCO Abstract #3008 Hodi. Slide 19
Ipilimumab Patterns of Response (1): Responses in Baseline Lesions Patient treated with 10 mg/kg ipilimumab in study CA184-007 50 153 Change from baseline SPD (%) 25 0 25 50 75 100 Complete Response (mwho) 135 117 99 82 64 46 28 10 8 SPD (mm 2 ) 125 26 9 3 3 9 15 21 27 33 39 45 51 57 63 69 75 Relative week from randomisation date Ipilimumab Dosing SPD = sum of the product of the perpendicular diameters 1 st Tumor Assessment Week 12 Source: 2008 ASCO Abstract #3008 Hodi. Slide 20
Ipilimumab Patterns of Response (2): Stable Disease with Slow, Steady Decline in Total Tumor Burden SPD = sum of the product of the perpendicular diameters Source: 2008 ASCO Abstract #3008 Hodi. Slide 21 Ipilimumab Dosing
Slide 22 Ipilimumab Patterns of Response (3): Response after Initial Increase in Total Tumor Burden Patients treated with 10 mg/kg ipilimumab in study CA184-008 Progression (mwho) 6+ months Index + New Lesion Index Lesion New Lesion Ipilimumab Dosing SPD = sum of the product of the perpendicular diameters Source: 2008 ASCO Abstract #3008 Hodi.
Ipilimumab Patterns of Response (3): Response after Initial Increase in Total Tumor Burden Patient treated with 10 mg/kg ipilimumab in study CA184-008 Screening Week 12: Initial increase in total tumor burden (mwho PD) Week 14: Responding Week 16: Response Follow-up ongoing Source: 2008 ASCO Abstract #3008 Hodi. Slide 23
Ipilimumab Response Patterns (4): Response After the Appearance and Subsequent Disappearance of New Lesions Patients treated with 10 mg/kg ipilimumab in study CA184-008 Progression (mwho) 10+ months New lesion shrinking SPD = sum of the product of the perpendicular diameters Source: 2008 ASCO Abstract #3020 Wolchok. Slide 24
Slide 25 Ipilimumab Response Patterns (4): Responses After the Appearance and Subsequent Disappearance of New Lesions Pre-treatment Week 12: Progression 10 mg/kg ipilimumab Q3W X 4 New lesions Week 20: Regression Week 36: Still Regressing Source: 2008 ASCO Abstract #3020 Wolchok.
Patterns of Response to Ipilimumab: Survival Benefit Comparable to mwho Pooled data from Phase 2 studies CA184-008 and CA184-022 (10 mg/kg ipilimumab, n=227) Proportion Alive CR=Complete Response, PR=Partial Response, SD=Stable Disease, PD=Progressive Disease Source: 2008 ASCO Abstract #3008 Hodi. Slide 26 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 10% 28% mwho 0 2 4 6 8 10 12 14 Months not considered by mwho 38% disease control mwho Criteria: CR/PR/SD 28% Ipilimumab Response Patterns: CR/PR/SD with mwho PD 10% PD under both Criteria 38% Early PD Without Follow-up 25%
Patterns of Response to Ipilimumab: Clinical Activity Not Fully Captured by mwho Criteria IRC Assessment at 12 weeks After 12 weeks mwho Disease Control in Baseline Lesions Week 12 (n=42) 27% mwho Response in Baseline Lesions Week 12 (n=10) mwho Stable Disease in Baseline Lesions Week 12 (n=32) Stable Disease with Slow, Steady Decline in Total Tumor Burden (n=15) Study 008 (N=155) Patients treated with 10mg/kg ipilimumab No Follow-up Scan (n=26) mwho PD at Week 12 (n=87) Followed Beyond mwho PD (n=43) 30% (13 of 43 patients) with clinical benefit beyond mwho PD Reported mwho assessments per Independent Review Committee (IRC). Source: Adapted from 2008 ASCO Abstract #9021 O Day. Slide 27
Overall Safety Profile Summary Ipilimumab therapy associated with immune-related adverse events (iraes) mechanism based Safety profile remains consistent with program-at-large iraes are dominant related adverse events 4 main categories: gastrointestinal/gi, skin, liver, endocrine Overall irae rate is ~70% High-grade (3/4) iraes rate is ~25% iraes generally manageable and reversible using established management guidelines Management guidelines effective in decreasing incidence of serious adverse events complications (e.g. gastrointestinal) Source: 2008 ASCO Abstracts #9021 O Day, #9025 Hamid, #9010 Weber, #9055 Thompson and #9063 Lin. Slide 28
Ipilimumab Safety Profile Consistent Over Program Study 008 (N=155) Study 022* (N=217) Study 007** (N=115) Dosing Regimen 10 mg/kg 10 mg/kg (n=72) 10 mg/kg + placebo ( n=57) 10 mg/kg + prophylactic budesonide (n =58) Median Overall Survival in months (95%CI) 10.2 (7.3, ) 14.6 (6.9, ) Not Reached (11.5, ) Not Reached (6.8, ) % Survival Rate at 1 year (95%CI) 46.7 (38.6, 5556) 53.4 (41.2, 63.7) 59.1 (45.4, 72.2) 58.8 (43.6, 70.3) % Disease Control Rate (95%CI) 27.1 (20.3, 34.8) 29.2 (19.0, 41.1) 35.1 (22.9, 48.9) 31.0 (19.5, 44.5) All iraes 70.3% 70.4% 84.2% 81.0% Grade 3/4 iraes Gastrointestinal Liver Endocrine Skin Other 21.9% 8.4% 7.1% 1.3% 3.2% 2.6% 25.4% 15.5% 2.5% 1.4% 4.2% 38.6% 22.8% 12.3% 5.3% 0% 41.4% 24.1% 10.3% 5.2% 5.2% Source: 2008 ASCO Abstracts #9020 O Day, #9025 Hamid, #9010 Weber, #9055 Thompson and #9063 Lin. Slide 29 * 10mg/kg cohort data shown. ** Includes subjects with and without prior systemic therapy.
Slide 30 Established Management Guidelines Example: Diarrhea Source: 2008 ASCO Abstract #9063 Lin.
Slide 31 Ipilimumab: Innovative, Active Agent Advancing Science Prolonged overall survival and one-year survival rates favorable compared to medical literature New response patterns were observed that were associated with survival mwho response criteria may not adequately capture clinical activity of ipilimumab New lesions may not always indicate progression or treatment failure Responses may occur after initial progression 10mg/kg is optimal ipilimumab dosing regimen with acceptable benefit : risk ratio Immune-related adverse events associated with mechanism of action Generally manageable and reversible using established treatment guidelines Broad development program as monotherapy and in combination with other treatment modalities
Slide 32 Ipilimumab Phase 3 Updates in Melanoma and Prostate Cancer Geoffrey M. Nichol, MBChB Senior Vice President, Product Development Medarex, Inc.
Slide 33 Ipilimumab Second-Line Registration Discussion: Submitted summary statistics and preliminary survival data in second-line studies (008, 022 and 007) to FDA to assess accelerated approval Target response rate data in second-line melanoma based on traditional mwho measured at as early as Week 24 not met in Study 008 Exploratory analysis to capture unique patterns of response not adequate for the basis of accelerated approval Overall survival (OS) data in absence of well-powered, controlled study cannot form the basis for accelerated approval OS data compared with historical control is not a reliable basis for accelerated approval Request additional OS data from Study 024 (first-line melanoma) Strong recommendation for OS from Study 024 (first-line melanoma) as the basis for a subsequent approval Continue compassionate use program (Study 045)
Slide 34 Ipilimumab Phase 3 Melanoma Update First-line DTIC Combination Phase 3 (study 024) Enrollment completed 1Q08 BMS amendment in process to change primary endpoint to overall survival FDA feedback expected 3Q08 No additional patients or interim analysis expected Data assessment and BLA timeline based on amendment discussion and event rate Adjuvant Phase 3 (study 029) Enrollment of 950 patients with EORTC Initiation expected summer 2008 Reviewing options for melanoma second-line submission outside US Commitment with BMS to continue Compassionate Use Program at this time
Slide 35 Ipilimumab Phase 3 Prostate Update Melanoma data considered to be positive Phase 2 proof-of-concept Compelling prostate Phase 2 data 11:30 a.m. CDT Oral Presentation on Monday 6/2 Location W375e ASCO 2008, Abstract #5004 Phase 3 program in taxotere-ineligible (failed or intolerant to docetaxel) Design is local radiotherapy ± Ipilimumab OS is primary endpoint Enrollment expected around YE08/early 2009
Slide 36 BMS and Medarex Committed to Development of Ipilimumab Program Melanoma Chemotherapy combination Phase 3 Adjuvant Phase 3 Monotherapy Phase 2 Prostate Radiotherapy combination Phase 3 Combination with other agents Phase 1/2 Prostate Phase 2/3 Additional Indications Ongoing Lung Cancer Phase 2 Pancreas Phase 2 Bladder Phase 2 Breast Phase 2 Leukemia Phase 1 Lymphoma Phase 1
Slide 37 Medarex Milestones Christian S. Schade Senior Vice President and Chief Financial Officer Medarex, Inc.
Slide 38 Q&A Session
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