Biogen Idec Oncology Pipeline Greg Reyes, MD, PhD SVP, Oncology Research & Development March 25, 2009
Biogen Idec Strategy in Lymphoma / Leukemia CLL RITUXAN NHL FC-RITUXAN GA101 RITUXAN-CVP RITUXAN-CHOP FCR-Lumiliximab Relapsed CLL R-Galiximab Relapsed NHL 2
RITUXAN Chimeric mab That Binds To and Kills CD20-Expressing Cells Rituxan ADCC Macrophage, monocyte, or natural killer cell FcγRII, FcγRIII CD20 Cell lysis B cell CDC MAC Cell lysis Apoptosis 2009: RITUXAN submissions in Chronic Lymphocytic Leukemia REACH Study: Relapsed CLL CLL8 Study: Frontline CLL Golay et al. Blood. 2000;95:3900; Reff et al. Blood. 1994;83:435; Byrd et al. Blood. 2002;99:1038. 3 ADCC = antibody-dependent cellular cytotoxicity CDC = complement-dependent cytotoxicity
REACH and CLL8 Study Design in CLL Screening REACH: Relapsed CLL ~550 patients (First relapse of disease); 90 sites, 17 countries Randomize R-FC x 3 cycles (q 4 weeks) Restage FCR x 3 cycles (q 4 weeks) Binet B,C ~820 patients; (No prior treatment) FC x 3 cycles (q 4 weeks) PD- Off study FC x 3 cycles (q 4 weeks) CLL8: Frontline CLL Screening 4
REACH Primary Endpoint: K-M Plot of PFS Proportion Event Free 1.0 0.8 0.6 0.4 0.2 FCR FC Median follow-up 25.3 months Median PFS FC= 21.7 months FCR= 26.6 months HR = 0.76, p=0.02 (IRC) 0 0 6 12 18 24 30 36 42 48 54 Months since randomization 5
CLL8 Primary Endpoint: K-M Plot of PFS Median Follow-up 25.5 Months Median PFS: FC= 32.3 months FCR =42.8 months p=0.000007 6
Summary: RITUXAN for the Treatment of CLL REACH Relapsed CLL Median PFS = 21.7 months for FC vs. 26.6 months for FCR (p=0.02 by IRC) CLL8 Frontline CLL Median PFS =32.3 months for FC vs. 42.8 months for FCR (p=0.000007) Both studies significant in both CR and ORR No new or unexpected safety signals consistent with RITUXAN safety profile from other studies MABTHERA (trade name for RITUXAN in the Europe) approved for the front-line treatment of CLL in combination with FC in February 2009 Dual submission of both CLL8 and REACH planned in the US by mid 2009 7
GA101: Third generation anti-cd20 program Preclinical data suggest that GA101 may be better than RITUXAN Increased apoptosis and ADCC Higher affinity for FcγRIIIa receptors In several models, prevents regrowth compared with RITUXAN which temporarily suppresses More effective in depleting B-cells Both degree and duration of depletion in NH primates Goal: Develop a best-in-class anti-cd20 therapy leading to a significant improvement in clinical outcomes for patients with B cell malignancies. 8
B Cell Depletion in NH Primates: GA101 vs. RITUXAN 200 Inguinal ( Lymph ) Nodes Abs numbers/mg wt.(x10e3) 180 160 140 120 100 80 60 40 20 Vehicle Rituximab (2 x 10 mg/kg) GA101 (2 x 10 mg/kg) GA101 (2 x 30 mg/kg) 0 Baseline 2 9 35 Days After Dosing Umana et al., 2007 ASH Meeting, Atlanta, GA 9
CD23 and Lumiliximab Mechanism of Action Human constant Regions (IgG1 kappa isotype) Macaque variable regions CD23 Overview CD23 is the low affinity receptor for IgE (FcεRII) Functions to regulate IgE synthesis CD23 is highly expressed and abnormally regulated on CLL cells Lumiliximab is a monoclonal antibody that binds human CD23 with high affinity (Kd = 0.12nM) Lumiliximab Mechanism of Action Predominant MOA is apoptotic cell death via the intrinsic mitochondrial pathway Induces down-regulation of anti-apoptotic proteins including Bcl-2, Bcl-XL, Mcl-1, and XIAP in CLL cells Enhances the apoptotic activity of other anticancer drugs from a number of different classes Adapted from Gould and Sutton Nat. Rev. Immunol.. 2008 10
Lumiliximab Enhances Apoptosis when Combined with Fludarabine or RITUXAN In Vitro Efficacy (SKW 6.4 cells plus cross-linker) In Vivo Efficacy (disseminated lymphoma SCID mouse model) % Apoptotic Cells Caspase-3 activation (%) 60 50 40 30 20 10 0 80 60 40 20 0 Untreated Untreated Isotype Ctrl Isotype Ctrl Lumiliximab Lumiliximab Fludarabine Lumi + Flu 1 20 1 20 1 20 RITUXAN Lumi + Ritux Lumiliximab + fludarabine Lumiliximab + RITUXAN Dose (μg/ml) 11 Survival (%) Survival (%) 100 80 60 40 20 Lumiliximab + Fludarabine Lumiliximab (200 μg) Fludarabine (50 mg/kg) Control 0 10 20 30 40 50 60 Days Following Implant 100 80 60 40 20 0 Control Lumiliximab + RITUXAN RITUXAN (200 μg) Lumiliximab (200 μg) 20 40 60 80 Days Following Implant
Lumiliximab Clinical Program Lumiliximab Monotherapy Ph 1 dose escalation in Relapsed CLL Well-tolerated at all doses studied Evidence of clinical activity in majority of patients Recommended dose for future studies, 500 mg/m2 At doses 375 mg/m2, CD23 sites on CLL cells were saturated 500 mg/m2 dose resulted in longest duration of receptor saturation No relationship between dose and adverse events Lumiliximab +/- FCR Ph 1/2 and 2/3 (LUCID) in Relapsed CLL; Ph 2 in CLL Frontline (LIFT) Rationale for FCR combination regimen: In vitro and in vivo studies demonstrated improved cytotoxic activity of lumiliximab in combination with fludarabine or rituximab Fludarabine, cyclophosphamide and rituximab (FCR) has emerged as the standard of care for the treatment of CLL. Ph I/II study demonstrated a 52% complete response (CR) in relapsed CLL, more than twice the CR rate of FCR alone in historical controls, 12
Phase II/III, Lumiliximab in Combination With FCR (LUCID) Patient Eligibility (n=900) Relapsed CD23+/CD20+ B-cell CLL 1-2 prior therapies Rai stage III/IV Stage I/II with disease progression Patients not refractory to FC, FR or FCR 6 cycles Lumiliximab + FCR FCR Phase II Complete response endpoint Enrollment complete 390 Pts Phase III Progression-free survival endpoint Strategy for accelerated approval: CR and trend in PFS 13 Note: Study 152-201
Lumiliximab (anti-cd 23 mab) Molecule Molecular Hypothesis First-in-Class Monoclonal Antibody Targeting CD23 Demonstrated apoptotic cell death as primary MOA and may be potentially effective at overcoming resistance generally seen in CLL Enhanced apoptotic activity in combination with common CLL therapies, fludarabine and rituximab Therapeutic Hypothesis Addition of a well-tolerated pro-apoptotic agent to current SOC treatment will offer greater efficacy without additional toxicity.. Potential Indications Stage Chronic lymphocytic leukemia, small lymphocytic lymphoma Preclinical combination studies ongoing Global Registrational Phase 2/3 trial ongoing in relapsed CLL. Lumiliximab as a critical component of standard therapy, essential for maximizing response and thereby extending longevity and Quality of Life in patients with CLL 14
CD80 Expressed on NHL tumor cells Role in Regulating Balance Between Immune Activation and Suppression Background Transmembrane glycoprotein Member of the B7 ligand family (B7.1) 1 Involved in activation and regulation of T- cells 2 Transiently expressed on activated B- cells and antigen presenting cells 3 Plays a role in the regulation and activation of normal and malignant B- cells 1 Therapeutic Hypothesis In addition to direct ADCC-mediated killing of CD80-positive malignant B-cells, galiximab may also inhibit tumor progression by targeting non-malignant, CD80-expressing cells present in the tumor microenvironment (e.g., macrophages, dendritic cells). This may result in an alteration of the cellular composition and/or cytokine profile within the tumour microenvironment that favors inhibition of tumor progression Constitutively expressed on malignant B- cells and Reed-Sternberg cells 4 1. Suvas S et al. J Biol Chem 2002;277:7766 7775 2. Guinan EC et al. Blood 1994;84:3261 3282 3. Chambers CA & Allison JP. Curr Opin Cell Biol 1999;11:203 210 4. Munro JM et al. Blood 1994;83:793 798 15
Enhanced Anti-Tumor Activity and Improved Survival in Galiximab Immuno-chemo Combination Therapy SKW disseminated human lymphoma model 100 Gali+Ritux+Doxo Percent Survival 80 60 40 20 Doxo Neg Control IgG1 Doxo injections Antibody injection Ritux Gali + Ritux Ritux + Doxo 0 0 10 20 30 40 50 60 Days Post Implant Hariharan et al. J Clin Onc 2007;25(18S): abstract 3040; T. Murphy study G-3 16
Galiximab Clinical Trials in Lymphoma Relapsed Follicular NHL Monotherapy, Ph I/II in Relapsed Follicular NHL (114-20) Clean safety profile; 4/37 (11%) ORR; Late conversions of PRs to CRs Galiximab + RITUXAN, Ph I/II in Relapsed Follicular NHL (114-21) No increased toxicity; 12.2 month Median PFS compared to 9.4 months for historical RITUXAN monotherapy Galiximab + RITUXAN, Ph III in Relapsed f NHL (114NH301, ongoing) 245 subjects randomized as of March 2, 2009 Galiximab + RITUXAN, Ph III in Relapsed f NHL re-treatment (114NH302, ongoing) Frontline NHL Monotherapy, Ph I (MOA) in Frontline Follicular NHL (114NH103) Galiximab + RITUXAN, Ph II in Frontline f NHL (CALGB-sponsored, 50402, ongoing) Ongoing: 70% ORR, 44% CR/CRU, 12 month DFS 87%; Delayed responses in >15% of PR to CR conversion after 9 mos. of treatment Hodgkin s Monotherapy, Ph II in Relapsed Hodgkin s disease (CALGB-sponsored, 50602, ongoing) 17
Phase I/II Galiximab Monotherapy: Study 114-20 Single Agent Responses Delayed time to best response seen in 4 patients Phase I/II dose-escalating study 4 weekly IV infusions (125, 250, 375, or 500 mg/m2) 37 patients treated (9 received the commercial dose of 500 mg/m2) Overall response rate of 11% (4 of 37 patients) 375 mg/m2 (N = 21): 2 CRs, 1 Baseline Study Month 5 Study Month 12 PR; 500 mg/m2 (N = 10): 1 PR Delayed time to best response seen in the four responders (at 3, 6, 9 and 12 months) Duration of response was 22.7 months 18
Efficacy Results (Galiximab + RITUXAN) vs. RITUXAN Event-Free Survival (%) 100 90 80 70 60 50 40 30 20 10 0 C Ph 1/2 in Relapsed NHL (114-21) Historical Control: RITUXAN monotherapy median EFS = 9.4 mo. Galiximab + RITUXAN median EFS = 12.2 mo. 0 6 12 18 Time (Months) Median Age (yrs) Male Stage III/IV Disease Largest Tumor (cm) Median Max # Prior Regimens Median Max RITUXAN Naïve Galiximab + RITUXAN (500 mg/m 2 ) (N=64) 59 52 % 88 % 4.2 2.0, 16.0 2 1, 9 42 % Historical RITUXAN Monotherapy (N=243) 56 57 % 83 % 4.0 0.5, 15.0 2 1, 9 77 % More RITUXAN Naïve in HX control Note: Historic Rituxan EFS data are truncated at 24 months 19
TARGET Study (114NH301) Phase III Galiximab + RITUXAN Screening Randomization ~742 patients (First relapse of disease) 4 weekly cycles RITUXAN (375 mg/m2) + placebo RITUXAN (375 mg/m2) + galiximab (500 mg/m2) Follow-up to month 48 Conducted at 220 sites in 28 countries Nearly 250 patients randomized (more than a third of total) Primary endpoint - superiority in PFS with Galiximab + RITUXAN compared with RITUXAN 20
Galiximab (anti-cd 80 mab) Molecule Molecular Hypothesis Therapeutic Hypothesis Potential Indications Stage First-in-Class Monoclonal Antibody Targeting CD80 Binding to CD80 induces antibody dependent mediated cellular cytotoxicity (ADCC), synergistic with rituximab Constitutive expression on malignant B-cells and R-S cells Immune mechanisms regulating anti-tumor activity may also contribute to efficacy (APCs and activated B cells) Galiximab will have a role as adjunctive therapy for the treatment of CD80-expressing malignancies including relapsed Follicular Lymphoma based on a direct anti-tumor effect and its unique action on the tumor microenvironment Primary Indication: Relapsed follicular NHL Other: Untreated follicular NHL, DLBCL, Hodgkin s disease Phase 3 Generate rigorous mechanistic and clinical data in support of registration for Relapsed Follicular Lymphoma and establish the rationale for treatment of other CD80 expressing malignancies 21
Biogen Idec Oncology Pipeline Oncology RITUXAN Galiximab Lumiliximab Volociximab HSP90 Inhibitors GA101 TYSABRI Anti-IGF-1R Anti-Cripto-DM4 RAF Inhibitor Anti-Fn14 Pre-Clinical Phase 1 Phase 2 Phase 3 Market NHL & CLL (Ph 3 complete, filings 2009) NHL CLL Solid tumors Solid tumors NHL & CLL Multiple Myeloma Solid tumors Solid tumors Solid tumors Solid tumors January 2007 Pipeline 2007 and 2008 Progress 22
Biogen Idec Research & Development Day March 25, 2009