Clinical: Ipilimumab (MDX-010) Update and Next Steps

Transcription

1 Clinical: Ipilimumab (MDX-010) Update and Next Steps Geoffrey M. Nichol, M.D., M.B.A. Senior Vice President, Product Development Medarex, Inc. R&D Day December 9, 2005 Ipilimumab: New Class of Cancer Therapy Oncology immunopotentiator with potential broad application Important biological role as negative regulator for activated T cells Emerging market High potential return, limited competitive set Potential to become backbone of emerging multi-billion dollar cancer market Novel mechanism of action for biologic Potential to sustain long-term memory response 1

2 Ipilimumab: Summary of Clinical Development Experience to date in over 630 patients treated Overall melanoma development program in over 300 patients treated and evaluable for efficacy Active as monotherapy and in combination with other immunotherapies and chemotherapy Durable responses in patients with extensive disease (including CNS disease) longest response ongoing over 3 years No complete responses have relapsed to date Clinical responses associated with immune-mediated adverse events Activity in multiple tumor types (renal, NHL, ovarian, prostate) Broad development program with Bristol-Myers Squibb Ipilimumab: Summary of Response Data in Melanoma 3 mg/kg Ipilimumab Dose Combination Therapy Overall Response Rate Complete Response Duration of Response (months) Single Dose Phase I/II 2/17 (12%) 0 4, 4 Multi-Dose Phase II IL-2 5/24 (21%) 2 (8%) CR: 17+, 17+ PR: 17+, 14+, 11 Multi-Dose Phase II DTIC 6/35 (17%) 2 (6%) CR: 20+, 17+ PR: 21+, 4, 3, 3 Multi-Dose Phase II MDX /29 (14%) 2 (7%) CR: 40+, 40+ PR: 43+, 4 2

3 Ipilimumab: DTIC Combination Phase II Trial Design in Melanoma First-line, metastatic/unresectable melanoma * Dacarbazine can optionally be continued 2 additional months Treated Patients Arm A 37 patients Arm B 35 patients Follow Up Monthly X 3 Q3mo 2 years Source: Abstract #7525, ASCO Ipilimumab: DTIC Combination Phase II Trial Overall Survival Data 100% 75% MDX-010 (11.2 months) 50% MDX-010+DTIC (14.8 months) MDX-010 MDX DTIC Historical DTIC Censored data 25% 0% Months after Randomization Source: Abstract #7525, ASCO

4 Ipilimumab: DTIC Combination Phase II Trial Response Data 3 mg/kg Ipilimumab Monotherapy (n=37) 3 mg/kg Ipilimumab plus DTIC (n=35) DTIC (Historical Data)* Overall Response Rate 5.4% PR18+, PR % CR20+, CR17+, PR21+, PR4, PR3, PR3 3.6% 1 Duration 4.25 months Progression- Free Survival 2.7 months 3.3 months 1.6 months 1-5 Overall Survival 11.2 months 14.8 months 6.4 months 2-5 GI Events (All Grades) 43% (5% SAE) 71% (14% SAE) N/A * Sources: 1 FDA CDER Oncologic Drugs Advisory Committee May 3-4, Avril MF et al., JCO 22: , Middleton MR, et al., JCO 18: , Serrone L et al, J Exp Clin Canc Res 19:21-34, Eggermont AM et al., Eur J Cancer 40: , Source: Abstract#7525, ASCO Ipilimumab: Experience in Other Cancers Cancer Type 3 mg/kg Ipilimumab Combination Therapy Responses Single Dose Phase I 2/14 (14%, PSA) Prostate Multiple Dose Phase II Low Dose Taxotere In Review Multiple Dose Phase I/II GVAX Ongoing Breast Multiple Dose Phase II In Review Ovarian Renal Multiple Dose Phase I/II Multiple Dose (Prior IL-2) Phase II Multiple Dose (No Prior IL-2) Phase II Prior Autologous GVAX 2 / 6 PR (33%) 1 / 24 (4%) 4 / 18 (22%) Pancreatic Multiple Dose Phase II Ongoing Follicular Lymphoma Dose Phase I/II Ongoing Leukemia & Lymphoma Dose-escalation Phase I Post Allo-HCT ASH

5 Ipilimumab: Renal Monotherapy Phase II Response Data Experience at the National Cancer Institute Cohort Overall Response Responses Durations (in months) 3.0mg/kg 1.0mg/kg (n=21) 3.0mg/kg (n=40) 1 of 21 (4.7%) 6 of 40 (15%) PR18 PR18+, PR14+, PR9+, PR14, PR12, PR8 Grade 3/Grade 4 immune-mediated adverse events in 32.8% of patients Sources: Update reported by S.A. Rosenberg at isbtc 2005; Abstract#2501, ASCO Ipilimumab: GVAX Experience in Ovarian Ipilimumab CA GVAX 3/25/03 5/25/03 7/25/03 9/25/03 11/25/03 1/25/04 3/25/04 5/25/04 7/25/04 9/25/04 11/25/04 1/25/05 3/25/05 5/25/05 7/25/05 9/25/05 Sources: Update reported at isbtc 2005; Hodi et al. PNAS Apr; 100(8):

6 Ipilimumab: Expansion into Multiple Cancers Investigational Studies Planned Colorectal NSCLC Breast Bladder Objective Responses Observed Leukemia Lymphoma Ovarian Prostate Renal Ipilimumab: Registrational Program in Melanoma Multiple registrational pathways Combination with vaccine, second-line Monotherapy, second-line Combination with DTIC, first-line Identify biomarkers that predict patient response Assess potential prophylaxis of immune-mediated events and efficacy Evaluating range of submission opportunities targeting between 2007 and

7 Ipilimumab: MDX-1379 Vaccine Combination Phase III Trial Design in Melanoma Second-line, metastatic/unresectable melanoma N = 750 patients total (1:3:1) Final Analysis MDX-1379 Alone, n=150 Ipilimumab + MDX-1379, n=450 Ipilimumab Alone, 3 mg/kg, n=150 Final ORR Analysis Long Term F/U BLA Filing on Best Objective Response (primary endpoint) Ongoing analysis for disease progression, survival (secondary endpoints) Trial enrollment completion expected 2H06 Ipilimumab: Monotherapy Second-Line Registrational Study in Melanoma Single-arm study in metastatic melanoma 150 patients expected, all HLA-A2 types Dosing: 10.0mg/kg every 3 weeks x4, then every 3 months thereafter Endpoints: response rate, response duration Initiation expected 1Q06 7

8 Ipilimumab: Monotherapy Second-Line Supportive Study in Melanoma Blinded dose-ranging study in metastatic melanoma HLA-A2 negative patients (predominantly from current Phase III trial sites) 3-arm study, 70 patients per arm Dosing: 0.3, 3.0 and 10.0mg/kg every 3 weeks x4, then every 3 months thereafter Endpoints: response rate, response duration, progression-free survival, survival Initiation expected 1Q06 Ipilimumab: DTIC Combination First-Line Registrational Study in Melanoma 500 patients expected with metastatic melanoma Dosing: 10.0mg/kg every 3 weeks x4, with or without DTIC, then 10.0mg/kg ipilimumab every 3 months Endpoints: percentage of patients with progress-free survival at 12 weeks; ongoing analysis for survival Initiation expected 1Q06 8

9 Ipilimumab: Expansion into Multiple Cancers Investigational Studies Planned Colorectal NSCLC Breast Bladder Objective Responses Observed Leukemia Lymphoma Ovarian Prostate Renal Multiple Registrational Pathways in Melanoma First-line, DTIC Combination Second-line, Monotherapy Second-line, Vaccine Combination Ipilimumab: Manageable Safety Profile Expected immune-mediated adverse events (mechanism based) Key events organ specific most often colitis, dermatitis, pituitary inflammation Considerable experience in the diagnosis and management Highly correlated with clinical response 9

10 Ipilimumab: Clinical Responses Associated with Colitis as Immune Breakthrough Events (IBEs) Experience at the National Cancer Institute % Response Rate Melanoma Colitis Present 36% (8 of 22) Colitis Absent 11% (12 of 108) p= RCC 35% (6 of 17 ) 2% (1 of 42) p= All 36% (14 of 39) 9% (13 of 150) p< Source: Data reported at isbtc Conference, November IBEs by Target Organ* Majority of patients have either no adverse events (42%) or low grade adverse events (42% grade 1 or grade 2) GI Skin Ocular Liver Rare perforations and/or colectomies: <1% in over 630 patients treated Grade 3, 4 Grade 1, 2 Pituitary Other *Includes patients with IBEs involving more than one organ system 10

11 Evolving Management of IBEs Majority readily medically manageable and resolve without sequelae Steroid-refractory colitis reversible with infliximab (anti-tnfα antibody) in 6 of 7 patients Ipilimumab: Prophylactic Budesonide Phase II Study in Melanoma 100 patients expected with metastatic melanoma Randomized, double-blind, placebo-controlled with or without prophylactic oral budesonide Endpoints: rate of grade 2,3, 4 diarrhea; assess at week 24 best objective response, disease control rate, progression-free survival and overall survival Open for enrollment 11

12 Ipilimumab: Biomarker Study in Melanoma 80 patients expected with metastatic melanoma Randomized to 3.0 and 10.0mg/kg groups Endpoints: safety and efficacy; biopsy and immune response Initiation expected 4Q05 Ipilimumab: Broad Potential with Other Synergistic Combination Chemotherapy Immunotherapy (IL2, vaccines, IFNα, GM-CSF) Hormone blockade T reg depletion Radiation therapy Antibodies (i.e. anti-pd1 and others) Small molecule inhibitors 12

13 Ipilimumab: Summary First in a new class of oncology immunopotentiator Multiple options for registration in melanoma targeting between 2007 and 2008 Durable responses with monotherapy and in combination with other cancer therapies Broad exploratory programs in multiple tumor types 13