Research & Development Day

Transcription

1 Research & Development Day May 5, 2015 The Chatwal Hotel, New York

2 Forward-Looking Statements Disclaimer This presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of Words such as "may," "will," "expect," "plan," "anticipate" and similar expressions (as well as other words or expressions referencing future events or circumstances) are intended to identify forward-looking statements. These forward-looking statements reflect FivePrime's current beliefs and expectations. Each of these forward-looking statements involves risks and uncertainties. Actual results may differ from these forward-looking statements. Forwardlooking statements contained in this presentation include statements about (i) the timing of initiation, progress and scope of clinical trials for our product candidates; (ii) the timing of receipt of clinical results for our product candidates; (iii) the potential use of our product candidates to treat patients; (iv) the extent of gene amplification and protein overexpression in certain patient populations; (v) the advancement of our immuno-oncology program; and (vi) the period during which we expect to be able to fund operations. Many factors may cause differences between current expectations and actual results, including unexpected safety or efficacy data observed during preclinical or clinical studies, clinical site activation rates or clinical trial enrollment rates that are lower than expected, changes in expected or existing competition, failure of our collaborators to support or advance collaborations or product candidates and unexpected litigation or other disputes. Other factors that may cause our actual results to differ from current expectations are discussed in FivePrime's filings with the U.S. Securities and Exchange Commission, including the "Risk Factors" sections contained therein. Except as required by law, we assume no obligation to update any forward-looking statements contained herein to reflect any change in expectations, even as new information becomes available. 2

3 Agenda Time Topic Speaker 8:30 AM Welcome & Introductions Aron Knickerbocker 8:35 AM Company Platform & Strategy Rusty Williams, MD, PhD 8:45 AM FPA008 Overview Julie Hambleton, MD Brian Wong, MD, PhD Bob Sikorski, MD, PhD 9:20 AM Cancer immunotherapy and macrophages Antoni Ribas, MD, PhD 9:50 AM PVNS Robert Maki, MD 10:20 AM FPA144 Overview Kristen Pierce, PhD Julie Hambleton, MD 10:40 AM Gastric Cancer Charles Fuchs, MD, MPH 11:15 AM Immuno-Oncology Discovery Program Brian Wong, MD, PhD 11:45 AM Final Q & A Aron Knickerbocker 3

4 Investment Highlights 3 clinical-stage protein therapeutics covering 11 indications Competitive advantage in immuno-oncology Unique discovery platform for novel targets and protein drugs Clinical and research collaborations with BMS Platform generates assets valued by pharma; strong track record of deal-making Strong cash position sufficient to move all 3 clinical programs beyond significant inflections and to move new IO candidates into clinical trials 4

5 Platform: A Library of Substantially All Extracellular Proteins to Identify New Targets and Therapeutics Library of > 5700 Extracellular Proteins Proprietary Screens Protein Therapeutics Secreted Factors Cell-based Screens Ligand Traps (Soluble Receptors) In vivo Screens Receptors Receptor-Ligand Matching Novel Targets are Validated and drugged Antibodies Soluble Receptors 5

6 Clinical Pipeline: 3 Protein Therapeutics Covering 11 Indications INDICATIONS PRE-IND PHASE 1 PHASE 1B FPA008 CSF1R antibody 6 cancers in combination with Opdivo (nivolumab) PVNS Rheumatoid Arthritis FPA144 FGFR2b antibody Gastric Cancer Partnered FP-1039 (GSK ) FGF ligand trap Squamous NSCLC Mesothelioma 6

7 FP-1039 Selectively Blocks FGFR1 Ligands Cancer Promoting FGFs Selectively blocks cancerpromoting FGFs that bind to FGFR1, not unrelated FGFs FP-1039 Tumor Cell Tumor cell growth Tumor cell survival FGFR1 FGFR1 amplification in sqnsclc is associated with diminished survival Safe and well-tolerated as monotherapy in Phase 1; target engagement demonstrated Avoids retinal detachment, hyperphosphatemia, mucositis, nailbed changes and asthenia seen with small molecule TKIs 7

8 GSK-Funded Phase 1b Clinical Trial of FP-1039/GSK (Study FGF117360) Global study enrolling 70 to 120 patients FGFR1 amplification (10-20%) Squamous NSCLC 1 st line, paclitaxel/carboplatin Previously treated, docetaxel Safety and tolerability in combination with SOC FGF2 ligand over-expression Mesothelioma 1 st line, cisplatin/pemetrexed Dose/PK Overall Response Rate & Duration GSK plans to report preliminary efficacy data by EOY

9 Expectations PROGRAM INDICATION STATUS FPA008 CSF1R antibody 6 Cancers Complete Phase 1a dose escalation & expand to Phase 1b by late 2015/early 2016 PVNS Initial data by late 2015 to early 2016 RA Present open-label RA data by end of 2015 FPA144 FGFR2b antibody Gastric Cancer Initial data from solid tumor & unselected gastric cancer patients by end of 2015 FP-1039 FGF ligand trap Squamous NSCLC & Mesothelioma GSK to present preliminary efficacy data by end of 2015 Immuno-Oncology Research Cancer Advance internal drug candidates to preclinical development 9

10 FPA008 Antibody for Macrophage-Dependent Diseases Julie Hambleton, MD SVP & Chief Medical Officer

11 FPA008 Blocks Activation and Survival of Macrophages by Blocking Ligand Binding to CSF1R FPA008 CSF-1 CSF-1R IL-34 (Discovered by FivePrime) Macrophages/Monocytes/Osteoclasts Survival Activation 11

12 FPA008 Testing in 3 Macrophage Disease Settings Monocytes Tumor-Associated Macrophages Monocytes/Macrophages in Joints Inflammatory Macrophages, Osteoclasts Immuno-Oncology Pigmented Villonodular Synovitis (PVNS) Rheumatoid Arthritis 12

13 FPA008: Completed Phase 1 Testing in Healthy Volunteers FPA008 was well tolerated up to 3 mg/kg No DLTs All adverse events were low grade and reversible Periorbital edema was noted at 3 mg/kg and 10 mg/kg Expected event; Class effect of unknown etiology Elevations of serum enzymes Expected based on nonclinical studies No pathologic changes despite high doses and prolonged exposure in animal studies - does not represent damage to muscle or liver Related to decrease in liver macrophages (Kupffer cells) and resultant decrease in serum enzyme clearance Shown by Five Prime & others (Radi et al., Am. J. Pathol. 2011, 179: ) 13

14 In Mid-2015, FPA008 Will Be in 3 Disease Settings Cancer in combination with nivolumab: Phase 1a: Dose escalation, safety and biomarkers Phase 1b: Expansion in 6 different cancers to test efficacy PVNS: Phase 1/2 in this CSF1-driven disease RA: Dose escalation, safety & preliminary assessment of MRI 14

15 FPA008 Program: Today s Presentations Topic IO Rationale Clinical Development Summary Cancer immunotherapy and macrophages Tenosynovial giant cell tumor (TGCT) / pigmented villonodular synovitis (PVNS): Treatment landscape Presenter Brian Wong, MD, PhD Bob Sikorski, MD, PhD Antoni Ribas, MD, PhD Robert Maki, MD 15

16 FPA008 IO Rationale Brian Wong, MD, PhD VP of Research & Head of Immuno-Oncology

17 Rationale to Target Tumor-Associated Macrophages for Cancer Immunotherapy Infiltrating CD68+ tumor-associated macrophages (TAMs) correlate with poor outcome in a variety of solid and heme malignancies TAMs potently suppress T cell effector function through release of immunosuppressive cytokines and factors cell surface inhibitory factors Targeting TAMs efficacious in animal tumor models Myeloid signature associated with resistance to T cell checkpoint inhibition therapy References: Ries et al., (2014) Cancer Cell, 25: ; Pyonteck et al., (2013) Nat Med, 19: ; Zhu et al., (2014) Cancer Res., 74: ; Roche presentation ASCO 2014: Inhibition of PD-L1 by MPDL3280A in metastatic urothelial bladder cancer 17

18 Tumor Associated Macrophages (TAMs) Are Associated with a Poor Prognosis in Many Cancers Pancreatic Cancer Overall Survival TAMs associated with poor outcome in solid tumors TAM high TAM low Months Post Surgery Yoshikawa et al. Cancer Sci Squamous NSCLC Adenocarcinoma NSCLC Melanoma HNSCC Glioma Pancreatic Bladder RCC Ovarian HCC Komohara et al. Cancer Sci

19 TAMs Potently Suppress T Cells Tumor Checkpoints Soluble factors Proliferation (CPM) 100K 80K 60K 40K 20K Isolated TAMs Inhibit T Cell Proliferation 0 TAMs T Cells TAM:T cell ratio Movahedi et al. Cancer Res

20 Suppressive Tumor Associated Macrophages Form at the Invasive Front in Colorectal Carcinoma Tumor Llosa et al. Cancer Disc Invasive front 20

21 CSF1R Blockade Reduces TAMs Control Mouse FPA008 Mouse Tumors TAM Staining (F4/80) 20x 20x Recently published data demonstrate that CSF1R blockade reduces TAMs in multiple human tumors 21

22 CSF1R Inhibition Synergizes with Checkpoint Inhibitors Pancreatic tumor model Tumor regression Zhu et al., (2014) Cancer Research 22

23 CSF1R Antibody Synergizes with an Immune Agonist Control Mouse FPA008 Anti-CD40 Combo FGK45 * Anti-CD40 * p< Mouse FPA008 Potential to combine with a variety of IO modalities 23

24 FPA008 Clinical Development Summary Robert Sikorski, MD, PhD VP, Global Clinical Development

25 Ongoing FPA008 Phase 1: Transitioned from Healthy Volunteers into RA Patients Part 1 Single Ascending Dose Part 2 Dual Ascending Dose Part 3 in RA Open Label (N=9) Randomized (N=30) 10 mg/kg 6 mg/kg Active dose 1 (N=12) 3 mg/kg 3 mg/kg 3 mg/kg Active dose 2 (N=12) 3 mg/kg 1 mg/kg 1 mg/kg 0.2 mg/kg 1 mg/kg Placebo (N=6) 25

26 FPA008 PK Results Support q2-3 Week Dosing Serum FPA008 (µg/ml) Single IV Dose 0.2 mg/kg 1 mg/kg 3 mg/kg 10 mg/kg LOQ Time (w) 26

27 FPA008 Adverse Events Were All Grade 1-2 & Reversible Preferred Term Placebo (N=8) n (%) 0.2 mg/kg (N=6) n (%) 1 mg/kg (N=6) n (%) 3 mg/kg (N=6) n (%) 10 mg/kg (N=6) n (%) Pruritus 1 (13%) 4 (67%) 3 (50%) 4 (67%) Eyelid Edema 4 (67%) 5 (83%) Headache 1 (13%) 3 (50%) 1 (17%) 1 (17%) 3 (50%) Fatigue 2 (25%) 1 (17%) 1 (17%) 2 (33%) 2 (33%) Local Swelling 5 (83%) Facial Swelling Pruritus Generalized 5 (83%) 2(33%) 1 (17%) Vision Blurred 3 (50%) 27

28 Transient Elevation of AST After FPA008 Treatment 135 3X ULN AST (U/L) X ULN 1X ULN Time (hour) Post Dose Serum AST for All Normal Human Volunteer Subjects in Part 1 and 2 28

29 Transient Elevation of ALT After FPA008 Treatment 204 3X ULN ALT (U/L) X ULN 1X ULN Time (hour) Post Dose Serum ALT for All Normal Human Volunteer Subjects in Part 1 and 2 29

30 Normal Bilirubin After FPA008 Treatment 87 3X ULN TBIL (µmol/l) X ULN 1X ULN Time (hour) Post Dose Serum Total Bilirubin for All Normal Human Volunteer Subjects in Part 1 and 2 30

31 A Single Dose of FPA008 Causes Rapid and Sustained Reduction of CSF1R+ Target Monocytes in Humans CD16-positive monocytes per µ L blood Placebo FPA008 1 mg/kg FPA008 3 mg/kg FPA mg/kg W eeks 31

32 FPA008 Causes a Dose-Dependent Reduction of Bone Turnover Biomarkers in Healthy Volunteers Trap5b Trap5b Part 1 CTx CTx Part 1 Serum Trap5B (% Pre-Dose) mg/kg 1 mg/kg 3 mg/kg 10 mg/kg Placebo Serum CTx (% Pre-Dose) mg/kg 3 mg/kg mg/kg 10 mg/kg Placebo Time (w) Time (w) 32

33 FPA008 is Being Developed in Multiple Clinical Indications RA Open Label IND Cleared 4/15/15 Phase 1/2 PVNS Phase 1a/b anti-pd1 Combinations 33

34 FPA008 Pigmented Villonodular Synovitis (PVNS)

35 PVNS is a Locally Destructive Tumor Affecting Joints Normal Knee PVNS Knee PVNS Macrophages CSF1 driven disease No approved systemic therapy Logical setting for anti-csf1r therapy 35

36 FPA008 PVNS Phase 1/2 Trial Design z mg/ kg (n 3-6) (n 3-6) y mg/ kg N = 30 x mg/ kg (n 3-6) Dose Escalation Characterize safety Characterize PK Identify recommended dose for expansion Dose Expansion MRI at month 1, and q 2 thereafter Establish response rate and duration Evaluate pain, joint function 36

37 Five Prime is Designing an Epidemiology Study to Better Characterize the Prevalence of PVNS PVNS is an ultra orphan disease Prevalence and incidence are not well characterized Plan to use a patient registry that has been used to support previous regulatory filings 37

38 FPA008 Immuno-Oncology

39 FPA008 + Nivolumab Phase 1a/b Combination Trial Demonstrated nivolumab activity Non-small cell lung cancer Melanoma Head & neck Exploratory Pancreatic cancer Colorectal cancer Malignant glioma 39

40 FPA008 + Nivolumab Combination Trial Design Phase 1a 1) FPA008 monotherapy Phase 1b NSCLC 1 Second/Third Line a mg/kg b mg/kg Melanoma 2 Anti-PD1 naïve Advanced cancers Safety objective SCCHN 3 Second Line 2) FPA008 + nivolumab GBM 4 First Recurrence z mg/kg Pancreatic 5 Second Line y mg/kg x mg/kg CRC 6 Third Line Advanced cancers Safety objective 3+3 design Blood-based PD marker Translational A Translational B 40

41 Evaluating the Local Tumor Microenvironment is Essential in Immuno-Oncology Drug Development Multiple interactions govern responses to immunotherapy CSF1R Visualization of immune infiltrate and tumor architecture (each color represents a different marker) TAM PD-1 PD-L1 Treg CD8 T Cell PD-1 PD-L1 Tumor cell Sample Image: Perkin Elmer Vectra Automated Quantitative Pathology Imaging System; 41

42 Analysis of the Tumor Microenvironment Will Guide FPA008 Development in Cancer Patients Pre treatment biopsy at screening Post treatment biopsy one month after therapy Additional biopsies of selected subjects Next generation tissue analysis: Multiparameter IHC TCR clonality Neoepitope mapping 42

43 FivePrime vs Roche CSF1R x PD1 Pathway Trial Comparison FivePrime Trial FPA008 (anti CSF1R ligand blocking Ab) + Nivolumab (anti PD1) Roche Trial (NCT ) RO (anti CSF1R dimerization blocking Ab) + MPDL3280A (anti PDL1) NSCLC Melanoma SCCHN Pancreatic Colorectal GBM Triple negative breast Ovarian Bladder Gastric Soft tissue sarcoma 43

44 FPA008 is Being Developed in Multiple Clinical Indications RA Open Label IND Cleared 4/15/15 Phase 1/2 PVNS Phase 1a/b anti-pd1 Combinations 44

45 Expected FPA008 Program Milestones RA Present open-label Phase 1 data by end of 2015 PVNS Dose initial subjects in Phase 1/2 trial in mid 2015 Immuno-oncology Dose initial nivolumab combination patients in mid 2015 Complete Phase 1a dose escalation & expand to Phase 1b by late 2015/early

46 Antoni Ribas, MD, PhD

47 Cancer immunotherapy and macrophages Antoni Ribas, M.D., Ph.D. Professor of Medicine Professor of Surgery Professor of Molecular and Medical Pharmacology Director, Tumor Immunology Program, Jonsson Comprehensive Cancer Center (JCCC) University of California Los Angeles (UCLA) Chair, Melanoma Committee at SWOG

48 Inhibiting PD-1-mediated adaptive immune resistance Anti-PD-1 Anti-PD-L1 Melanoma cell or tumor macrophage Interferons Taube et al. Sci Transl Med 2012 Tumeh et al. Nature 2014

49 Inhibiting PD-1-mediated adaptive immune resistance Anti-PD-1 Anti-PD-L1 Melanoma cell or tumor macrophage Interferons Tumeh et al. Nature 2014

50 PD-L1 positive macrophages inhibiting T cells in tumors SOX-10 (red nucleus) PD-L1 (brown membrane) Yellow arrows: PD-L1+ melanoma cells Red arrow: PD-L1+ lymphocytes (high nuclear:cytoplasmic ratio) Green arrows: PD-L1+ macrophages (low nuclear:cytoplasmic ratio) Tumeh et al. Nature 2014

51 PD-L1 positive macrophages inhibiting T cells in tumors Paul Tumeh, unpublished

52 Management of cancer in the post-anti-pd-1/l1 era Anti-PD-1/anti-PD-L1 Bring T cells into tumors: Generate T cells: + anti-ctla4 + immune activating antibodies or cytokines + TLR agonists or oncolytic viruses + macrophage or IDO inhibitors + targeted therapies Vaccines TCR engineered ACT CAR engineered ACT

53 SM1: A BRAF V600E -driven Melanoma Syngeneic to Immunocompetent Mice Goel, Haluska et al. Oncogene CGH array showing chromosomal aberrations in SM1 similar to human melanomas Chromo some BRAF V600E mutation Cdkn2a Braf Mitf CNV comparing SM1 with 108 human melanomas CDKN2A BRAF MITF

54 High Expression Secreted proteins expressed by SM1 1. S100a6 16. Gmfb 31. Ltbp2 46.Pdgfb 61.Tgfb3 76.Figf 91.Ngf 106.Il17re Low Expression 2. Cyr Slit2 32.Cmtm7 47.Rabep1 62.Vegfc 77.Pthlh 92.Pdgfra 107.Ccl9 Spp1 Ereg Cx3cl1 Sema7a Ogn Cxcl10 Ptn 108. Bmp4 Mif Inhba Il6st Bdnf Tor2a Oxt Sema3f Hdgf Cxcl1 Cmtm3 Vegfa Ccl7 Il13ra1 Insl6 Tnc Cxcl12 Lif Cklf Edn1 Il17ra Artn Hbegf Sbds Cat Il17rc Il11ra1 Lrsam1 Pdgfd Csf1 Pdgfa Igf2 Cmtm6 Sema6d Sema4b Btc Fgf7 Nampt Jag1 Il1r1 Apln Stc2 Igf1 Grn Pdgfrb Vegfb Il15ra Il17rd Tnfsf12 Sema3c Ltbp3 Rabep2 Hdgfrp3 Ccl5 Nppb Sema4c Nrtn Ctgf Clcf1 Txlna Tgfb2 Gdnf Il7 Ctf1 Pdgfc Il1rl1 Bmp1 Bmp2 Ccl20 Ltbp4 Il Ccl2 29.Cd Il10rb 59.Plau 74.Sema3a 89.Il1rap 104.Il6ra 15. Ltbp1 30.Il18rap 45.Nenf 60.Areg 75.Ccl25 90.Il Cmtm5 Stephen Mok, Ashley Cass, Tom Graeber

55

56 CSF-1R inhibitor

57 Combined anti-tumor activity of adoptive cell transfer (ACT) immunotherapy and CSF1R inhibitor CSF1R inh CSF1R inh CSF1R inh S. Mok et al. Cancer Research 2014

58 Changes in intratumoral macrophages in responses to PLX3397 CSF1R inh CSF1R inh F4/80 (MΦ) DAPI CSF1R inh CSF1R inh CSF1R inh

59 CSF1Ri

60 Conclusions PD-1 blockade works by inhibiting adaptive immune resistance leading to the expansion of intratumoral T cells Antitumor T cells are inhibited by PD-L1 expressed by cancer cells and intratumoral macrophages Blocking CSF1R results in decrease in intratumoral macrophages and improvement of T cell responses to cancer The preclinical data supports the testing of combined therapy with anti-pd-1 and anti-csf1r

61 Robert Maki, MD

62 Tenosynovial giant cell tumor (TGCT) / pigmented villonodular synovitis (PVNS): Treatment landscape Robert Maki, MD PhD FACP Director, Sarcoma Program Professor of Medicine, Pediatrics, and Orthopaedics Mt Sinai Medical Center New York, NY

63 Tenosynovial giant cell what? That s what pathologists said, too Synonyms: Localized type Localized tenosynovial giant cell tumor Giant cell tumor of tendon sheath Nodular tenosynovitis Fibrous histiocytoma of tendon sheath Diffuse type Intra-articular diffuse type tenosynovial giant cell tumor Diffuse pigmented villonodular synovitis Miettinen M et al. Modern Soft Tissue Pathology; Cambridge Univ Press 2010

64 Sample joint: the knee Normal, happy synovium

65 Things we may all know a little about

66 TGCT / PVNS not so pretty Are you surprised these can recur?

67 TGCT / PVNS so what are they? Inflammatory appearing growths around or into a joint cavity TGCT / localized: most common in fingers PVNS / diffuse: knee, hip most common Lots of inflammatory cells under the microscope Most common in 4th decade Incidence 1-2 per million US: / yr

68 TGCT / PVNS so what are they? Surprise: they are not just inflammatory! Connective tissue malignancy Part of the family of tumors called sarcomas Very low to no metastatic potential Lots of local damage and morbidity Uses an inflammatory signal (CSF1) as a beacon for the immune system Nearly 100% are driven by a specific DNA change t(1;2) COL6A3-CSF1 CSF1 turned on in every cell A near-perfect target for something that blocks CSF1 binding to its receptor West RB et al. PNAS 2006; 103: 690

69 Targeting CSF1 in TGCT with FPA008 or oral kinase inhibitors CSF1 fusion protein Cell membrane Translation and secretion CSF1R (CD115) mrna FPA008; Imatinib; PLX3397 Nucleus t(1;2) COL6A3- CSF1 West RB et al. PNAS 2006; 103: 690

70 Within 2 years of the t(1;2) data weeks + 5 months Blay J-Y et al. Ann Oncol 2008; 19: 821

71 Imatinib in a larger group of patients Imatinib 400 mg oral daily n=29, two with metastatic disease 5/27 with RECIST PR (19%) 16/22 with symptoms had improvement 6/29 stopped for toxicity; 4 stopped for no clear medical reason Continuous application seemed necessary to maintain good clinical result Cassier PA et al. Cancer 2012;118:1649

72 Newer data: oral PLX3397 Small molecule oral kinase inhibitor CSF1R > other kinases inhibited, IC50~17 nm Phase I, n=21 efficacy population 2/3 with knee TGCT primary site mg oral daily = 1000 mg at MTD AEs: Fatigue, hair color change, nausea, vomiting, anorexia, change in taste, periorbital edema, diarrhea, LFT Tap WD et al. Proc ASCO 2014: Abstr 10503

73 Swimmer s plot: oral PLX3397 PR 12/20 = 60% SD 7/20 = 35% PD 1/20 = 5% 79% with tumor volume reduction over 50%, mean 61% Tap WD et al. Proc ASCO 2014: Abstr 10503

74 mab data: RG7155 mab prevents CSF1R dimerization N=18 evaluable at time of presentation 9/18 with knee primary site Ultimate dose: 1000 mg IV q 2 weeks 6/18 had prior imatinib or nilotinib 15/18 evaluable patients with RECIST PR Uncommon G3 AEs: Periorbital edema, mucositis CD14+ CD16+ monocytes decreased in blood Cassier PA et al. Proc ASCO 2014: Abstr 10504

75 RG7155: TGCT shrinking over time Cassier PA et al. Proc ASCO 2014: Abstr 10504

76 The drugs work! How to give them? Recurrent disease Continuous administration traditional approach Maximize benefit therapy for 6-12 months, then stop, and restart as needed Will you induce drug resistance? High risk primary disease Diffuse type TGCT, esp hip, knee Can you cure people who would otherwise recur? Is GIST an analogy here too? (1, 3 years adj Rx)

77 How long do we have to wait for results? Recurrence by completeness of resection Proportion without recurrence Proportion without recurrence Palmerini E et al. Eur J Cancer 2015; 51: 210 Recurrence by primary vs recurrent disease

78 Summary There is a clear link between the genetic aberration of TGCT/PVNS and drugs that target CSF1 signaling FPA008 is well poised for success given the present findings with CSF1R targeted therapy Competition in PLX3397, RG7155 > imatinib, other mabs or TKIs Like bevacizumab in melanoma, can FPA008 also serve as a novel agent in immunotherapy?

79 gmail.com

80 FPA144 A Humanized Monoclonal Antibody to FGFR2b for Gastric Cancer Kristen Pierce, PhD Director, Project Team Leader

81 FPA144 - A Humanized Monoclonal Antibody to FGFR2b Splice Variant for Gastric Cancer Causes tumor regression in animal models Lead indication is FGFR2b over-expressed gastric cancer Companion diagnostic will identify patients most likely to respond Asn 297 Blocks ligand binding to FGFR2b Enhanced Antibody Dependent Cell Cytotoxicity (ADCC) 81

82 Fibroblast Growth Factors Are Alternatively Spliced FGF Ligand Turner and Grose,

83 FGFR Biology FGF Ligands Classical FGFs KGF Sub-family Hormonal FGFs FGF Receptors Klotho Klotho 1b 1c 2c 3b 3c 4 2b 1c 4 Blocked by FP-1039 Blocked by FPA144 Spared by Both FGFR tyrosine kinase inhibitors indiscriminately block all FGFRs 83

84 The FGFR2 Gene Is Amplified in Gastric Cancer The FGFR2 gene is amplified in a sub-set of gastric cancer (~5%). FGFR2 is the only gene in this amplicon. FGFR2 fluorescence in-situ hybridization (FISH) assay employs two fluorescently conjugated probes: FGFR2 (red in example below) and centromere control (green) FGFR2-Amplified Non-Amplified 84

85 Both FGFR2 Amplification and Over-Expression in Gastric Cancer Are Associated with Poor Prognosis FGFR2 gene amplification or FGFR2 protein over-expression is associated with lower survival in gastric cancer patients Most commonly found in patients with diffuse, poorly differentiated gastric cancer FGFR2 Gene Amplification FGFR2 Protein Over-Expression Cumulative Survival FGFR2 negative FGFR2 positive Jung et al. 2009; FGFR2 FISH; P=0.012 Hattori et al. 1996; FGFR2 IHC; P=0.15 Data are for all disease stages, including early 85

86 FPA144: Antibody to FGF Receptor 2b with Enhanced Cell Killing for Gastric Cancer Natural Killer Cell FGF7, 10, 22 FPA144 FGFR2b Tumor Cell FPA144 is engineered for enhanced ADCC Recruits natural killer (NK) cells more effectively than native antibody Incorporates BioWa s POTELLIGENT glycoengineering technology 86

87 FPA144 has Impressive Activity at Low Doses In FGFR2- Amplified Gastric Cancer Xenografts SNU-16 higg Mouse FPA144 FPA144 Tumor Volume (Mean mm 3 ±SEM) OCUM2 Albumin FPA144 5mg/kg FPA144 3 mg/kg FPA144 2 mg/kg FPA mg/kg FPA144 1 mg/kg Days Post Tumor Implantation 5 mg/kg twice weekly Dose Complete Regression 5 mg/kg 8/15 3 mg/kg 5/15 2 mg/kg 1/ mg/kg 2/15 1 mg/kg 0/15 Dosing twice weekly 87

88 FPA144 Has Additive Activity in Combination With Chemotherapy OCUM2 Tumor Volume (Mean mm 3 ±SEM) Tumor Volume 1200 Albumin FPA FU/Cisplatin FPA144 +5FU/Cis Days Post Tumor Implantation FPA144 5 mg/kg twice weekly Chemo=MTD Dosing started when tumors reached ~250 mm 3 Albumin/Vehicle Paclitaxel/Albumin FPA144/Vehicle FPA144/Paclitaxel 88

89 FPA144 Diagnostic Strategy for Patient Selection FGFR2b protein overexpression FGFR2 gene amplification IHC Five Prime s proprietary IHC antibody Distinguishes FGFR2b and 2c Validated by LabCorp FISH Positive - FGFR2 probe: centromere probe 2 Validated by LabCorp 89

90 FPA144 Clinical Development Julie Hambleton, MD SVP & Chief Medical Officer

91 FPA144 Phase 1 Study Now Enrolling Patients Part 1A: Dose escalation in solid tumors; 3+3 design Assess safety, PK Identify recommended or maximally tolerated dose Part 1B: Unselected gastric cancer Part 2: Expansion into biomarkerselected gastric cancer patients FISH-positive (~5%) FISH-negative, IHC-positive Measure safety, response rate Assess safety, PK 91

92 FPA144 Has Potential for Accelerated Development High unmet need in the refractory setting; potential for accelerated development and U.S. approval as monotherapy Potential combination trial with other anti-cancer agents Potential development in other cancers, such as cholangiocarcinoma (translocation in ~13%) Companion diagnostic plans Assessing IHC & FISH in Phase 1 Explore blood-based assays, such as cell-free DNA sequencing (NGS) 92

93 FPA144 Development Path: Monotherapy & in Combination with Standard of Care Today Monotherapy in Refractory Setting IND Phase 1 Phase 1, Part 2: Monotherapy Pivotal Single Arm Monotherapy Phase 2 Japan Phase 1 Potential for Accelerated Approval Combination Studies Phase 1b Pivotal Frontline Study 93

94 FGFR2 Competitive Landscape and FPA144 Advantages Competitive Agent FGFR TKIs (multiple) Target all 4 FGFRs Associated with dose limiting toxicities In Phase 1 & 2 testing FGFR2 Antibody (Bayer) Targets both FGFR2b & c isoforms In Phase 1 testing FGFR2-ADC (Bayer) Targets both FGFR2b & c isoforms Entering Phase 1 Potential Advantages of FPA144 Selective inhibition of FGFR2 pathway Expect superior therapeutic index Hyperphosphatemia and retinal toxicity not seen in preclinical studies Kill tumor cells by ADCC Selective for FGFR2b expect superior therapeutic index Enhanced for ADCC for greater tumor cell killing Selective for FGFR2b expect superior therapeutic index 94

95 FPA144 Program Expectations Begin dosing selected gastric cancer patients by EOY Initial data from Phase 1 by late 2015/early 2016 Safety, PK from Part 1A (solid tumor patients) Safety, PK from Part 1B (unselected gastric cancer patients) 95

96 Charles Fuchs, MD, MPH

97 Landscape of Therapies in Advanced Gastric Cancer Charles S. Fuchs, MD Dana-Farber Cancer Institute Harvard Medical School Boston, MA

98 Upper Gastrointestinal Cancer in the U.S.: 2015 Cancer Site Incidence Deaths Esophagus 16,980 15,590 Stomach 24,590 10,720 Worldwide Gastric cancer = 4 th common malignancy Second most common cause of cancer mortality

99 Gastric Cancer Mortality: Regional Differences per 100,000 population United States China Chile Japan Columbia Hungary Poland Venezuela Germany France 0 Jemal et al. CA Cancer J Clin :106.

100 Treatment of Metastatic Gastric Cancer Approximately two thirds patients present with advanced stage disease 1 The exception is Korea and Japan, where surveillance programs are widely practiced For advanced disease, palliative chemotherapy is the mainstay, and treatment combinations differ between geographical regions 1,2 Conventional chemotherapy has limited efficacy, with median survival of ~10 months 3 Predictive biomarkers could refine treatment strategies 3 HER: predictive biomarker for treatment with trastuzumab 4 1. Kim R, et al. Crit Rev Oncol Hematol. 2013;88(2):416 26; 2. Matsueda S, et al. World J Gastroenterol. 2014;20(7): ; 3. Lim SM, et al. World J Gastroenterol. 2014;20(8): ; 4. Bang YJ, et al. Lancet. 2010;376(9742):

101 Phase III chemotherapy trials leading to current standard practice in advanced gastric cancer Study Treatment (n) RR (95% CI) Median OS PFS TTP (95% CI) FAMTX (108) 21% (13-29) 5.7 mo 3.4 mo n/a Webb et al 1 45% (36-54) 8.9 mo 7.4 mo ECF (111) n/a (P=.0002) (P=.0009) (P=.00006) V325 2 CF (224) 25% ( ) DCF (221) 37% ( ) (P=.01) 8.6 mo (95% Ci ) 9.2 mo (95% CI ) n/a n/a 3.7 mo ( ) 5.6 mo ( ) S-1 (150) n/a 11.0 mo (IQR ) 4.0 mo (IQR ) n/a SPIRIT 3 CDDP + S-1 (149) n/a 13.0 mo (IQR ) 6.0 mo (IQR ) (P<0.0001) n/a 1. Webb A, et al. J Clin Oncol. 1997;15(1): Van Cutsem E, et al. J Clin Oncol. 2006;24(32): Koizumi W, et al. Lancet Oncol. 2008;9(3):215-21

102 Developing Targeted Therapies in Gastric Cancer

103 ToGA: A Randomized, Open Label Multicenter Phase III Study 3807 patients screened 810 HER2-positive (22.1%) Stratification factors Advanced vs. metastatic disease GC vs. GEJ Measurable vs. non-measureable ECOG PS 0-1 vs. 2 Capecitabine vs. 5-FU HER2-positive* advanced gastric or GEJ cancer (n=584) *IHC 3+ or FISH+ 5-FU=5-fluorouracil; GEJ=gastroesophageal junction; R=randomization; ECOG PS =Eastern Cooperative Oncology Group performance score. R Capecitabine 1 or iv 5-FU 2 + cisplatin 3 (n=290) Capecitabine or iv 5-FU 2 + cisplatin 3 + Herceptin (n=294) Chosen at investigator s discretion mg/m2 bid d1-14 q3w x 6 cycles mg/m2/day continuous iv infusion d1-5 q3w x 6 cycles 3 80 mg/m2 q3w x 6 cycles 4 8 mg/kg loading dose followed by 6 mg/kg q3w until disease progression Bang YJ, et al. Lancet. 2010;376:

104 ToGA Primary Endpoint: Overall Survival No. at risk Probability FC + Herceptin Events Median OS (mo) FC Time (months) HR 95% CI p-value F+C+Herceptin F+C , F=fluoropyrimidine (either fluorouracil or capecitabine); C=cisplatin. Bang YJ, et al. Lancet. 2010;376:

105 Role of VEGF Pathway in Tumor Growth Ramucirumab (IMC-1121B; RAM) is a recombinant human IgG1 monoclonal antibody receptor antagonist designed to bind the extracellular domain of VEGF Receptor-2, thereby blocking the binding of VEGF ligands and inhibiting receptor activation. VEGF-C VEGF-D VEGF binds to VEGFR2 receptor; VEGF-C, -D compete for binding to VEGFR2 VEGF-A Ramucirumab VEGFR2 VEGFR2 Endothelial cell membrane VEGF-A VEGF-C VEGF-D Ramucirumab binds to VEGFR2, blocks VEGF ligand binding Ligand binding activates VEGFR2 and p44/p42 MAP kinases No signaling Angiogenesis Tumor growth Inhibit new blood vessel formation and tumor growth

106 REGARD Study Design S C R E E N R A N D O M I Z E N = 355 2:1 Ramucirumab 8 mg/kg q2wk + BSC (n = 238) Placebo q2wk + BSC (n = 117) Treatment until disease progression or intolerable toxicity Tumor assessment, survival, and safety follow-up Multicenter, randomized, double-blind, placebo-controlled, phase 3 trial Gastric or GEJ adenocarcinoma Stratification factors: region, weight loss ( 10% vs. <10% over 3 months), location of primary tumor (gastric vs. GEJ) Global: 6 continents, 30 countries, 120 study centers Abbreviations: BSC=best supportive care; GEJ= gastroesophageal junction Fuchs et al. Lancet 2013

107 REGARD: Overall Survival Overall Survival HR (95% CI) = (0.603, 0.998) Log rank P-value (stratified) = Ramucirumab Placebo Patients / Events 238 / / 99 Median (mos) (95% 5.2 (4.4, 5.7) 3.8 (2.8, 4.7) CI) 6-month OS 42% 32% 12-month OS 18% 11% Ramucirumab Placebo Censored Censored No. at Risk Months Ram Plcb Fuchs et al. Lancet 2013

108 RAINBOW: Study Design S C R E E N 1:1 R A N D O M I Z E Ramucirumab 8 mg/kg day 1&15 + Paclitaxel 80 mg/m 2 day 1,8 &15 of a 28-day cycle N = 330 Placebo day 1&15 + Paclitaxel 80 mg/m 2 day 1,8 &15 N = 335 Treat until disease progression or intolerable toxicity Survival and safety follow-up Important inclusion criteria: - Metastatic or loc. adv. unresectable gastric or GEJ* adenocarcinoma - Progression after 1 st line platinum/fluoropyrimidine based chemotherapy Stratification factors: - Geographic region, - Measurable vs non-measurable disease, - Time to progression on 1 st line therapy (< 6 mos vs. 6 mos) * GEJ= gastroesophageal junction; gastric and GEJ will be summarized under the term GC

109 RAINBOW: Overall Survival 1.0 HR (95% CI) = (0.678, 0.962) Stratified log rank p-value = RAM + PTX PBO + PTX 0.8 Patients / Events 330 / / 260 Median(mos) (95% CI) 9.63 (8.48, 10.81) 7.36 (6.31, 8.38) month OS 72% 57% Overall Survival Probability RAM+PTX 12-month OS 40% 30% Δ mos = 2.3 months No. at risk PBO+PTX Censored Months RAM + PTX PBO + PTX

110 MET Amplification as a Predictor of Drug Sensitivity in Gastric and Esophageal Adenocarcinoma Graziano et al J Clin Onc 2011: 230 pts: 10% MET amplifications Worse prognosis Yapp et al J Clin Onc 2011: Phase I trial of ARQ197 Smollen et al PNAS, 2006 Minor regression in gastric cancer

111 RILOMET-1: Phase III trial of ECX +/- rilotumumab in MET-positive gastroesophageal adenocarcinoma 450 pts (estimated enrollment) with MET+ GE adenocarcinoma R A N D O M I Z E ECX + rilotumumab ECX + placebo Primary endpoint: overall survival Result: No benefit for Rilotumumab

112 Randomized Trial of Onartuzumab in Advanced Gastric Cancer Eligibility criteria Age >18 Metastatic GEC HER2 negative ECOG PS 0/1 No prior therapy for metastatic disease Tissue available N=123 R 1:1 mfolfox6* + onartuzumab (10 mg/kg) q2w N=62 12 cycles mfolfox6* + placebo q2w N=61 Onartuzumab Placebo PD PD Stratified by Lauren histologic subtype and prior gastrectomy Primary objectives: PFS in the ITT population and the MET-positive subgroup ( 50% high staining by IHC) Secondary objectives: OS (ITT and MET-positive population), ORR, safety With 120 patients enrolled and 84 PFS events observed, target HRs were 0.70 in the ITT population and 0.60 in the MET-positive subgroup Conducted over 30 sites across Australia, Korea, Singapore, Taiwan, Thailand and USA *Oxaliplatin 85 mg/m 2 + leucovorin 200 mg/m fluorouracil 400 mg/m 2 bolus and 2400 mg/m 2 iv Presented by: Manish Shah

113 Primary endpoint: PFS ITT MET-positive * PFS probability (%) Placebo + mfolfox6 (N=61) Onartuzumab + mfolfox6 (N=62) Censored Median PFS 6.77 vs 6.97 Stratified HR 1.06 (95% CI ) p= PFS probability (%) Placebo + mfolfox6 (N=19) Onartuzumab + mfolfox6 (N=16) Censored Median PFS 5.95 vs 6.8 Stratified HR 1.38 (95% CI ) p= No of patients at risk Placebo + mfolfox6 Onartuzumab + mfolfox Time (months) No of patients at risk Placebo + mfolfox6 Onartuzumab + mfolfox Time (months) The stratified HR for PFS in the MET-negative population was 0.99 (95% CI ) *50% staining cut-off; CI, confidence interval Presented by: Manish Shah

114 AMG337: Responses in Patients With MET-Amplified GEJ/Gastric/Esophageal Cancer % SOD From Baseline 80% 60% 40% 20% 0% -20% Time to response: On treatment: On active treatment 4wk 17wk 9wk 17wk 4wk +9wk Off treatment 4wk 29wk 4wk 25wk 4wk +96wk 4wk 4wk +21wk +155wk 13 patients with METamplified GEJ/gastric/ esophageal cancer treated to date; ORR = 8/13 (62%) -40% PR per RECIST 1.1 a -60% -80% -100% b a Local read as of Dec 8, b Local read as of Sept 10, Central read as of Sept 18, 2014 for all other patients. One patient not shown with nontarget lesions had 114 clinical progression.

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117 We are defining the genome of Esophageal and Gastric cancers.

118 Distinct Pattern of Focal Amplifications Between Upper/Lower GI Adenocarcinomas High-Level Amplifications Dulak, Schumacher et al Cancer Research 2012

119 Statistical analysis of focal amplifications across gut adenocarcinomas Cytoband Significant amplifications (across all gut adenocarcinomas) Residual q-value Peak Boundaries (Mb) Number of Genes in Peak Candidate Target(s) (Bold designates therapeutic target) Gut Adenocarcinoma Types Represented Gut Adenocarcinomas 12p E KRAS E, G 18q E GATA6 E, G, C 17q E ERBB2 E, G, C 19q E CCNE1 E, G 8q E MYC E, G, C 8p E GATA4 E, G 11q E CCND1, FGF3, FGF4, FGF19 E, G 7q E CDK6* E 6p E VEGFA E, G 7p E EGFR E, G 17q E E 9p E E 12q E MDM2, FRS2 E, G 7q E E 13q E E 10q E E 7q E MET E 1q E MCL1 E 1q E G 10q E FGFR2 E 13q E E 5/4/2015 BOLD= potential target

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121 Molecular Subtypes of GC and Key Features Ryo Sakai

122 CIN Tumors: Highly Recurrent Amplification of Oncogenes Nils Wilheim

123 FGFR2 Gene Amplification and Clinicopathological Features in Gastric Cancer British Journal of Cancer (2012) 106,

124 Phase I Trial AZD4547 in Advanced Gastric and GE Junction Cancer FGFR1-3 tyrosine kinase inhibitor 13 patients with FGFR amplification 1 partial response, 5 stable disease Hyperphosphatemia noted Arkenau et al. Proc ASCO /13 patients had retinal pigment epithelial detachment that led to dose interruptions or discontinuation Study did not meet pre-specified efficacy endpoint for continuation

125 Novel Targets for Gastric Cancer: 2015 Target HER2 Progress to date MoAb demonstrates efficacy (Trastuzumab); TKIs not proven beneficial; other strategies under development (TDM1; pertuzumab) VEGF, VEGFR2 Ramucirumab approved in 2014 MET PDL1 FGFR2 Trials based on IHC failed; preliminary data based on amplification suggest activity Preliminary signal for PD-1 MoAb; trials ongoing Initial efforts for TKIs not demonstrating convincing benefit; studies of MoAb ongoing

126 Immuno-Oncology Novel Drug Discovery Brian Wong, MD, PhD VP of Research & Head of Immuno-Oncology

127 Immuno-Oncology Is Transforming Cancer Treatment but Significant Opportunity Remains Opdivo (nivolumab) response rates Indication ORR Source Melanoma 32% CheckMate-037 SqNSCLC 15% CheckMate-063 RCC 29% JCO 2015 Ovarian 17% ASCO 2014 CRC 0% NEJM 2012 Consensus from KoLs: field is just scratching the surface 127

128 Many New IO Targets Remain to be Discovered in the Tumor Microenvironment Cell Surface Proteins Regulate Immune Responses to the Tumor T Cell Macrophage Tumor Cell 128

129 Our Vision: Develop New Therapies with a Global Understanding of Tumor Immunity Find All Tumor Immune Regulators And Their Binding Partners T Cell Inactive T Cell FP Novel FP Novel FP Novel FP Novel FP Novel Macrophage FP Novel FP Novel Immunome Genes Define Which Immune Regulators Operate in Which Tumors Cancer 1 Cancer 2 C3 Cancer 4 FP Novel Tumor Cell Tumor Cell Use this proprietary map to develop the best therapeutics for a defined patient population 129

130 Our Platforms Comprehensively Test All Cell Surface Proteins in the Tumor Microenvironment as Targets FPRX Immunome Library Contains substantially all cell surface proteins that regulate the tumor micro-environment Proprietary Screens Cell-based Screens In vivo Screens Antibody Targets Novel Checkpoints Immunome*: 500 Proteins *Proteins with motifs characteristic of checkpoints and immune regulators Receptor-Ligand Matching Novel Immune Activators Systematic & unbiased selection of the best functional immunome targets Goal: 1 IND per year starting in

131 Cell-Based Screening Led to A Novel Potent Regulator of Macrophages Proprietary Screens Cell-based Screens In vivo Screens Receptor-Ligand Matching Effect on Monocyte Proliferation IL-34, A Master Regulator of Monocytes and Macrophage Positive Control Known cytokines active IL-34 FivePrime protein library We identified CSF1R as the receptor for IL

132 We Are Screening for Novel Regulators of Immune Cells in the Tumor Microenvironment Inactive T Cell T Cell Macrophage Macrophage (TAMs) FPA008 was developed based on our discovery of IL-34 Effector T cells Find novel inhibitors (checkpoints) and block them with antibodies Tumor Cell Tumor Cell Regulatory T cells MDSC Dendritic Cells 132

133 A Screen for Novel T Cell Inhibitors (e.g. Checkpoints) Revealed Multiple Potential New Targets 27 initial hits were identified in a functional screen of the immunome for novel T cell checkpoints Example: Novel T Cell Checkpoint 1 shows similar or better potency to PDL1 in inhibiting T cells: 133

134 Novel T Cell Checkpoint 1 is Selectively Expressed on Effector CD4 + T Cells and Tregs Relative RNA Expression Across a Panel of Tissues and Immune Subsets Memory CD4 T cells Tregs Expression on the same T cell subsets is observed in tumors 134

135 T Cell Checkpoint 1 is a Potential Antibody Target Soluble Checkpoint 1 enhances tumor growth in an in vivo colon cancer model Control Novel Checkpoint 1 Results consistent with the ability of T Cell Checkpoint 1 to suppress T cell activation 135

136 An Antibody Blocking T Cell Checkpoint 1 Enhances T Cell Activation T Cell Interferon-γ production assay Interferon-γ Produced (Background subtracted) Checkpoint 1 Antibody Isotype Control We are generating fully human antibodies to T Cell Checkpoint 1 136

137 In Vivo Screening of the Entire Immunome for Regulators of the Tumor Microenvironment Proprietary Screens Cell-based Screens In vivo screens better model the tumor microenvironment Rapid in vivo expression of extracellular proteins bypasses protein scale up, purification, and formulation In vivo Screens Receptor-Ligand Matching Inject vector expressing Immunome library member Expressed proteins Syngeneic Tumor Model Measure tumor volume 137

138 Potential Immunome Hits Identified In an Ongoing In Vivo Tumor Screen Increased Tumor Growth Potential agonist hits Potential checkpoint hits Decreased Tumor Growth 150 of 500 immunome proteins tested to date 138

139 Identification of Ligands for Orphan Checkpoints Leads to New Targets and Enables Antibody Development Proprietary Screens Cell-based Screens In vivo Screens Receptor-Ligand Matching Many checkpoints do not have identified ligands such as B7-H3 and VISTA FivePrime is uniquely positioned to de-orphanize checkpoint regulators Rationale: Selection of the best therapeutic antibodies Patient selection markers Alternative targets Progress in de-orphanization and in initiating antibody campaigns 139

140 Summary Competitive advantage in discovering novel IO targets and therapeutics Progress made in finding novel T cell checkpoints and checkpoint binding proteins Expanding to additional regulatory cell types: Tregs and MDSC Ongoing in vivo screens are yielding potential targets Fully human antibody campaigns initiated to multiple targets with BMS, Adimab and Vaccinex Continue to provide updates at scientific conferences 140

141 Expectations PROGRAM INDICATION STATUS FPA008 CSF1R antibody 6 Cancers Complete Phase 1a dose escalation & expand to Phase 1b by late 2015/early 2016 PVNS Initial data by late 2015 to early 2016 RA Present open-label RA data by end of 2015 FPA144 FGFR2b antibody Gastric Cancer Initial data from solid tumor & unselected gastric cancer patients by end of 2015 FP-1039 FGF ligand trap Squamous NSCLC & Mesothelioma GSK to present preliminary efficacy data by end of 2015 Immuno-Oncology Research Cancer Advance internal drug candidates to preclinical development 141

142 Q&A

143 Research & Development Day May 5, 2015 The Chatwal Hotel, New York