research & development day€¦ · the advancement of our immuno- oncology program; and (vi)...

© 2015 Five Prime Therapeutics, Inc. All Rights Reserved

Research & Development Day

May 5, 2015The Chatwal Hotel, New York


Forward-Looking Statements Disclaimer

This presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. 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. Forward-looking 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.

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Agenda

Time Topic Speaker8:30 AM Welcome & Introductions Aron Knickerbocker8:35 AM Company Platform

& StrategyRusty Williams, MD, PhD

8:45 AM FPA008 Overview Julie Hambleton, MDBrian Wong, MD, PhDBob Sikorski, MD, PhD

9:20 AM Cancer immunotherapy and macrophages

Antoni Ribas, MD, PhD

9:50 AM PVNS Robert Maki, MD10:20 AM FPA144 Overview Kristen Pierce, PhD

Julie Hambleton, MD10:40 AM Gastric Cancer Charles Fuchs, MD, MPH11:15 AM Immuno-Oncology

Discovery ProgramBrian Wong, MD, PhD

11:45 AM Final Q & A Aron Knickerbocker

3


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


Platform: A Library of Substantially All Extracellular Proteins to Identify New Targets and Therapeutics

Receptor-LigandMatching

Antibodies

Ligand Traps(Soluble Receptors)

In vivoScreens

Soluble Receptors

Receptors

SecretedFactors

Library of > 5700Extracellular Proteins Proprietary Screens Protein Therapeutics

NovelTargets

areValidated

anddrugged

Cell-based Screens

5


INDICATIONS PRE-IND PHASE 1 PHASE 1B

FPA008CSF1R antibody

6 cancers in combination with Opdivo (nivolumab)

PVNS

Rheumatoid Arthritis

FPA144FGFR2b antibody

Gastric Cancer

Partnered

FP-1039(GSK 3052230)FGF ligand trap

Squamous NSCLC

Mesothelioma

Clinical Pipeline:3 Protein Therapeutics Covering 11 Indications

6


FP-1039 Selectively Blocks FGFR1 Ligands

• Selectively blocks cancer-promoting FGFs that bind to FGFR1, not unrelated FGFs

• 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 TKIsTumor cell growth

Tumor cell survival

Cancer Promoting FGFs

FP-1039

Tumor Cell

FGFR1

7


GSK-Funded Phase 1b Clinical Trial of FP-1039/GSK3052230 (Study FGF117360)

Safety and tolerability in combination

with SOC

Dose/PK

Overall Response Rate & DurationMesothelioma

1st –line, cisplatin/pemetrexed

FGF2 ligandover-expression

Squamous NSCLC• 1st line, paclitaxel/carboplatin• Previously treated, docetaxel

FGFR1 amplification(10-20%)

Global study enrolling 70 to 120 patients

GSK plans to report preliminary efficacy data by EOY 2015

8


Expectations



FP-1039FGF ligand trap

Immuno-Oncology Research

Gastric Cancer Initial data from solid tumor & unselected gastric cancer patients by end of 2015

Squamous NSCLC & Mesothelioma

GSK to present preliminary efficacy data by end of 2015

Cancer Advance internal drug candidates to preclinical development

INDICATION STATUSPROGRAM

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

9


FPA008Antibody for Macrophage-Dependent Diseases

Julie Hambleton, MDSVP & Chief Medical Officer


FPA008 Blocks Activation and Survival of Macrophages by Blocking Ligand Binding to CSF1R

SurvivalActivation

FPA008

Macrophages/Monocytes/Osteoclasts

CSF-1

IL-34(Discovered by

FivePrime)CSF-1R

11


FPA008 Testing in 3 Macrophage Disease Settings

Inflammatory Macrophages,Osteoclasts

Rheumatoid Arthritis

Immuno-Oncology

Tumor-Associated Macrophages

Monocytes

Pigmented VillonodularSynovitis (PVNS)

Monocytes/Macrophages in Joints

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http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&docid=0-6dt_ac1OltLM&tbnid=YAkBWQ3mtAXZsM:&ved=0CAUQjRw&url=http://www.rndsystems.com/ihc_molecule_images.aspx?m=3627&ei=aaVNU-_sGsqtyASJiIGYDQ&bvm=bv.64764171,d.aWc&psig=AFQjCNFxP27PE090-Pt8fUbfcYNHmrP3uQ&ust=1397683865567275

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&docid=0-6dt_ac1OltLM&tbnid=YAkBWQ3mtAXZsM:&ved=0CAUQjRw&url=http://www.rndsystems.com/ihc_molecule_images.aspx?m=3627&ei=aaVNU-_sGsqtyASJiIGYDQ&bvm=bv.64764171,d.aWc&psig=AFQjCNFxP27PE090-Pt8fUbfcYNHmrP3uQ&ust=1397683865567275


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: 240-247)

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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

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FPA008 Program: Today’s Presentations

Topic Presenter

IO Rationale Brian Wong, MD, PhD

Clinical Development Summary Bob Sikorski, MD, PhD

Cancer immunotherapy and macrophages


Tenosynovial giant cell tumor (TGCT) / pigmented villonodular synovitis (PVNS): Treatment landscape

Robert Maki, MD

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FPA008 IO Rationale

Brian Wong, MD, PhDVP of Research & Head of Immuno-Oncology


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, 25:846-859; Pyonteck et al., (2013) Nat Med, 19:1264-1272; Zhu et al., (2014) Cancer Res., 74: 5057-5069; Roche presentation ASCO 2014: Inhibition of PD-L1 by MPDL3280A in metastatic urothelial bladder cancer

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Tumor Associated Macrophages (TAMs) Are Associated with a Poor Prognosis in Many Cancers

TAMs associated with poor outcome in solid tumors

Squamous NSCLCAdenocarcinoma NSCLCMelanomaHNSCCGliomaPancreaticBladderRCCOvarianHCC

Pancreatic Cancer Overall Survival

Months Post Surgery

TAM low

TAM high

Komohara et al. Cancer Sci. 2013

Yoshikawa et al. Cancer Sci. 2012

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TAMs Potently Suppress T Cells

0

20K

40K

60K

80K

100K

TAM:T cell ratio

Isolated TAMs Inhibit T Cell Proliferation

Pro

lifer

atio

n (C

PM

)

Checkpoints

Soluble factors

TAMs T Cells

Tumor

Movahedi et al. Cancer Res. 2010

19


Suppressive Tumor Associated Macrophages Form at the Invasive Front in Colorectal Carcinoma

Llosa et al. Cancer Disc. 2015

Tumor

Invasive front

20


CSF1R Blockade Reduces TAMs

20x 20x

Mouse FPA008Control

TAM Staining (F4/80)

Mouse Tumors

Recently published data demonstrate that CSF1R blockade reduces TAMs in multiple human tumors

21


CSF1R Inhibition Synergizes with Checkpoint Inhibitors

Tumorregression

Zhu et al., (2014) Cancer Research

Pancreatic tumor model

22


CSF1R Antibody Synergizes with an Immune Agonist

Anti-CD40

Mouse FPA008

FGK45

ControlMouse FPA008Anti-CD40Combo

*

* p<0.0001

Potential to combine with a variety of IO modalities

23


FPA008Clinical Development Summary

Robert Sikorski, MD, PhDVP, Global Clinical Development


0.2 mg/kg

1 mg/kg

3 mg/kg

10 mg/kg

1 mg/kg

3 mg/kg

Part 1 Single Ascending Dose

Part 2 Dual Ascending Dose

Part 3 in RAOpen Label (N=9) Randomized (N=30)

Active dose 1 (N=12)

Active dose 2 (N=12)

Placebo (N=6)1 mg/kg

3 mg/kg

3 mg/kg

Ongoing FPA008 Phase 1: Transitioned from Healthy Volunteers into RA Patients

6 mg/kg

25


FPA008 PK Results Support q2-3 Week Dosing

0 1 2 3 4 5 6 7 8 9 10 11 12 13

1

10

100

Time (w)

Ser

um F

PA

008

(µg/

mL)

0.2 mg/kg1 mg/kg

LOQ

3 mg/kg10 mg/kg

300 Single IV Dose

26


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

5 (83%)

Pruritus Generalized

2(33%) 1 (17%)

Vision Blurred 3 (50%)

FPA008 Adverse Events Were All Grade 1-2 & Reversible

27


Transient Elevation of AST After FPA008 Treatment

0

45

90

135

0 72 144 216 288 360 432 504 576 648 720

AST

(U/L

)

Time (hour) Post Dose

1X ULN

2X ULN

3X ULN

Serum AST for All Normal Human Volunteer Subjects in Part 1 and 2

28


Transient Elevation of ALT After FPA008 Treatment

0

68

136

204

0 72 144 216 288 360 432 504 576 648 720

ALT

(U/L

)


1X ULN

2X ULN

3X ULN

Serum ALT for All Normal Human Volunteer Subjects in Part 1 and 2

29


Normal Bilirubin After FPA008 Treatment

0

29

58

87

0 72 144 216 288 360 432 504 576 648 720

TBIL

(µm

ol/L

)


3X ULN

2X ULN

1X ULN

Serum Total Bilirubin for All Normal Human Volunteer Subjects in Part 1 and 2

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A Single Dose of FPA008 Causes Rapid and Sustained Reduction of CSF1R+ Target Monocytes in Humans

0 1 2 3 4 5 6 7 8 9 1 0 1 1 1 20

2 0

4 0

6 0

8 0

1 0 0

1 2 0

W e e k s

CD

16

-po

sit

ive

mo

no

cy

tes

pe

rµ

L b

loo

d

P la c e b oF P A 0 0 8 1 m g /k gF P A 0 0 8 3 m g /k gF P A 0 0 8 1 0 m g /k g

31


FPA008 Causes a Dose-Dependent Reduction of Bone Turnover Biomarkers in Healthy Volunteers

Trap5b Part 1

Time (w)

Ser

um T

rap5

B(%

Pre

-Dos

e)

0 2 4 6 8 10 120

200

300 1 mg/kg3 mg/kg

0.2 mg/kg

100

10 mg/kgPlacebo

CTx Part 1

Time (w)

Ser

um C

Tx(%

Pre

-Dos

e)

0 2 4 6 8 10 120

50

150

200 1 mg/kg3 mg/kg

0.2 mg/kg

100

10 mg/kgPlacebo

CTxTrap5b

32


FPA008 is Being Developed in Multiple Clinical Indications

IND Cleared 4/15/15

Phase 1a/b anti-PD1 Combinations

Phase 1/2 PVNS

RA Open Label

33


FPA008Pigmented Villonodular Synovitis (PVNS)


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


FPA008 PVNS Phase 1/2 Trial Design

Dose Escalation

(n≈3-6)

(n≈3-6)

• Characterize safety• Characterize PK • Identify recommended dose for expansion

x mg/ kg

y mg/ kg

Dose Expansion

• MRI at month 1, and q 2 thereafter• Establish response rate and duration• Evaluate pain, joint function

N = 30

(n≈3-6)z mg/ kg

36


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


FPA008Immuno-Oncology


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


FPA008 + Nivolumab Combination Trial Design

40

• Advanced cancers• Safety objective• 3+3 design• Blood-based PD marker

x mg/kg

2) FPA008 + nivolumab

y mg/kg

z mg/kg

Phase 1a

• Advanced cancers• Safety objective

1) FPA008 monotherapy

a mg/kg

b mg/kg

Translational A Translational B

First Recurrence

Phase 1bNSCLC Second/Third Line

Melanoma Anti-PD1 naïve

SCCHN Second Line

Pancreatic Second Line5

6CRC Third Line

GBM

1

4

3

2

1

4

3

2


Evaluating the Local Tumor Microenvironment is Essential in Immuno-Oncology Drug Development

CD8T Cell

PD-1

TAM

PD-L1

Treg

CSF1R

Visualization of immune infiltrate and tumor architecture (each color

represents a different marker)

Multiple interactions govern responses to immunotherapy

Sample Image: Perkin Elmer Vectra Automated Quantitative Pathology Imaging System;

Tumorcell

PD-1

PD-L

1

41


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


FivePrime vs Roche CSF1R x PD1 Pathway Trial Comparison

FivePrime Trial Roche Trial (NCT02323191)FPA008 (anti CSF1R ligand blocking Ab)+ Nivolumab (anti PD1)

RO5509554(anti CSF1R dimerization blocking Ab)+ MPDL3280A(anti PDL1)

• NSCLC • Melanoma• SCCHN• Pancreatic• Colorectal• GBM

• Triple negative breast• Ovarian• Bladder• Gastric• Soft tissue sarcoma

43


FPA008 is Being Developed in Multiple Clinical Indications

IND Cleared 4/15/15

Phase 1a/b anti-PD1 Combinations

Phase 1/2 PVNS

RA Open Label

44


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 2016

45

Cancer immunotherapy and macrophages

Antoni Ribas, M.D., Ph.D.Professor of MedicineProfessor of Surgery

Professor of Molecular and Medical PharmacologyDirector, Tumor Immunology Program,

Jonsson Comprehensive Cancer Center (JCCC)University of California Los Angeles (UCLA)

Chair, Melanoma Committee at SWOG

Inhibiting PD-1-mediated adaptive immune resistance

Melanoma cellor tumor macrophage

Interferons

Anti-PD-1Anti-PD-L1

Taube et al. Sci Transl Med 2012Tumeh et al. Nature 2014

Inhibiting PD-1-mediated adaptive immune resistance

Melanoma cellor tumor macrophage

Interferons

Anti-PD-1Anti-PD-L1

Tumeh et al. Nature 2014

PD-L1 positive macrophages inhibiting T cells in tumors

SOX-10 (red nucleus) PD-L1 (brown membrane)

Yellow arrows: PD-L1+ melanoma cellsRed arrow: PD-L1+ lymphocytes (high nuclear:cytoplasmic ratio) Green arrows: PD-L1+ macrophages (low nuclear:cytoplasmic ratio)

Tumeh et al. Nature 2014

PD-L1 positive macrophages inhibiting T cells in tumors

Paul Tumeh, unpublished

Management of cancer in the post-anti-PD-1/L1 era

Anti-PD-1/anti-PD-L1

Generate T cells:

+ anti-CTLA4+ immune activating antibodies or cytokines+ TLR agonists or oncolytic viruses+ macrophage or IDO inhibitors+ targeted therapies

Bring T cells into tumors:

VaccinesTCR engineered ACTCAR engineered ACT

SM1: A BRAFV600E-driven Melanoma Syngeneic to Immunocompetent Mice

Goel, Haluska et al. Oncogene. 2009

BRAFV600E mutation

Chromosome

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

Cdkn2a Braf Mitf

CDKN2A BRAF MITF

CNV comparing SM1 with 108 human melanomas

CGH array showing chromosomal aberrations in SM1 similar to human melanomas

1. S100a6 16. Gmfb 31. Ltbp2 46.Pdgfb 61.Tgfb3 76.Figf 91.Ngf 106.Il17re

2. Cyr61 17. 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 Il34

14. Ccl2 29.Cd320 44.Il10rb 59.Plau 74.Sema3a 89.Il1rap 104.Il6ra

15. Ltbp1 30.Il18rap 45.Nenf 60.Areg 75.Ccl25 90.Il24 105.Cmtm5

High Expression

LowExpression

Secreted proteins expressed by SM1

Stephen Mok, Ashley Cass, Tom Graeber

CSF-1R inhibitor

Combined anti-tumor activity of adoptive cell transfer (ACT) immunotherapy and CSF1R inhibitor

S. Mok et al. Cancer Research 2014

CSF1R inh

CSF1R inh

CSF1R inh

Changes in intratumoral macrophages in responses to PLX3397

F4/80 (MΦ) DAPI

CSF1R inh

CSF1R inh

CSF1R inh

CSF1R inh

CSF1R inh

CSF1Ri

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


Robert Maki, MD

Tenosynovial giant cell tumor (TGCT) / pigmented villonodular synovitis

(PVNS): Treatment landscape

Robert Maki, MD PhD FACPDirector, Sarcoma Program

Professor of Medicine, Pediatrics, and OrthopaedicsMt Sinai Medical Center

New York, NY

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

Sample joint: the knee

Normal, happy synovium

Things we may all know a little about

TGCT / PVNS – not so pretty

Are you surprised these can recur?

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: 400-800 / yr

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 receptorWest RB et al. PNAS 2006; 103: 690

Targeting CSF1 in TGCT with FPA008or oral kinase inhibitors

t(1;2) COL6A3-

CSF1

mRNA

CSF1fusion protein

Nucleus

Translation and secretion

Cell membrane

FPA008; Imatinib;PLX3397

CSF1R (CD115)

West RB et al. PNAS 2006; 103: 690

Within 2 years of the t(1;2) data

0 + 10 weeks + 5 months

Blay J-Y et al. Ann Oncol 2008; 19: 821

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

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•600 + 400 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

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

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

RG7155: TGCT shrinking over time

Cassier PA et al. Proc ASCO 2014: Abstr 10504

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)

How long do we have to wait for results?

Recurrence by completeness of resection

Recurrence by primary vs recurrent disease

Palmerini E et al. Eur J Cancer 2015; 51: 210

Prop

ortio

n w

ithou

tre

curr

ence

Prop

ortio

n w

ithou

tre

curr

ence

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?

bobmakimd @ gmail.com


FPA144 – A Humanized Monoclonal Antibody to FGFR2b for Gastric Cancer

Kristen Pierce, PhDDirector, Project Team Leader


FPA144 - A Humanized Monoclonal Antibody to FGFR2b Splice Variant for Gastric Cancer

Blocks ligand binding to FGFR2b

Enhanced Antibody Dependent Cell Cytotoxicity (ADCC)

Asn297

• Causes tumor regression in animal models

• Lead indication is FGFR2b over-expressed gastric cancer

• Companion diagnostic will identify patients most likely to respond

81


Fibroblast Growth Factors Are Alternatively Spliced

FGF Ligand

Turner and Grose, 2010

82


FGFR Biology

Blocked by FP-1039 Blocked by FPA144

1c1b 1c 2c

FGF

Rec

epto

rsFG

FLi

gand

s

43b 3c 4

Klotho

Klotho

2b

1 2 3 4 5 6 8 9 11 12 13 14 16 17 18 20

7 10 22 19 21 23

“Classical” FGFs

KGF Sub-family

Hormonal FGFs

Spared by Both

FGFR tyrosine kinase inhibitors indiscriminately block all FGFRs

83


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


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

Jung et al. 2009; FGFR2 FISH; P=0.012 Hattori et al. 1996; FGFR2 IHC; P=0.15

FGFR2 Gene Amplification FGFR2 Protein Over-Expression

Data are for all disease stages, including early

444

Cum

ulat

ive

Surv

ival FGFR2 negative

FGFR2 positive

85


FPA144: Antibody to FGF Receptor 2b with Enhanced Cell Killing for Gastric Cancer

FPA144 is engineered for enhanced ADCC

• Recruits natural killer (NK) cells more effectively than native antibody

• Incorporates BioWa’s POTELLIGENT® glycoengineering technology

Natural Killer Cell

FPA144

Tumor Cell

FGFR2b

FGF7, 10, 22

86


FPA144 has Impressive Activity at Low Doses In FGFR2-Amplified Gastric Cancer Xenografts

SNU-16

Mouse FPA144FPA144

hIgG

OCUM2

0 20 40 600

200

400

600

800

1000

1200Albumin

FPA144 5mg/kg

FPA144 3 mg/kg

FPA144 2 mg/kg

FPA144 1.5 mg/kg

FPA144 1 mg/kg

Days Post Tumor Implantation

Tum

or V

olum

e(M

ean

mm

3 ±SE

M)

5 mg/kg twice weekly

Dosing twice weekly

Dose Complete Regression

5 mg/kg 8/15

3 mg/kg 5/15

2 mg/kg 1/15

1.5 mg/kg 2/15

1 mg/kg 0/15

87


FPA144 Has Additive Activity in Combination With Chemotherapy

Tumor Volume

10 15 20 25 30 35 400

200

400

600

800

1000

1200 AlbuminFPA1445FU/CisplatinFPA144 +5FU/Cis

Days Post Tumor Implantation

Tum

or V

olum

e(M

ean

mm

3 ±SE

M)

OCUM2

FPA144 5 mg/kg twice weeklyChemo=MTDDosing started when tumors reached ~250 mm3

Albumin/VehiclePaclitaxel/AlbuminFPA144/VehicleFPA144/Paclitaxel

88


FPA144 Diagnostic Strategy for Patient Selection

FGFR2 gene amplification

FISH

FGFR2b protein overexpression

IHC

• Five Prime’s proprietary IHC antibody• Distinguishes FGFR2b and 2c• Validated by LabCorp

• Positive - FGFR2 probe: centromere probe ≥2

• Validated by LabCorp

89


FPA144 Clinical Development

Julie Hambleton, MDSVP & Chief Medical Officer


FPA144 Phase 1 Study Now Enrolling Patients

FISH-positive (~5%)

Part 2:Expansion

into biomarker-selected gastric cancer patients

Part 1A: Dose escalation in solid tumors; 3+3 design

Measure safety,

response rateFISH-negative,

IHC-positive

Part 1B: Unselected gastric cancer

• Assess safety, PK • Identify recommended or

maximally tolerated dose

• Assess safety, PK

91


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


FPA144 Development Path: Monotherapy & in Combination with Standard of Care

IND

Phase 1, Part 2: Monotherapy

Pivotal Single ArmMonotherapy Phase 2

Phase 1

Pivotal Frontline Study

Mon

othe

rapy

in

Ref

ract

ory

Setti

ngC

ombi

natio

n S

tudi

es

Today

Potential for Accelerated

Approval

Japan Phase 1

Phase 1b

93


FGFR2 Competitive Landscape and FPA144 Advantages

Competitive Agent Potential Advantages of FPA144

FGFR TKIs (multiple)• Target all 4 FGFRs• Associated with dose limiting

toxicities• In Phase 1 & 2 testing

• Selective inhibition of FGFR2 pathway• Expect superior therapeutic index

• Hyperphosphatemia and retinal toxicity not seen in preclinical studies

• Kill tumor cells by ADCC

FGFR2 Antibody (Bayer)• Targets both FGFR2b & c isoforms• In Phase 1 testing

• Selective for FGFR2b – expect superior therapeutic index

• Enhanced for ADCC for greater tumor cell killing

FGFR2-ADC (Bayer)• Targets both FGFR2b & c isoforms• Entering Phase 1

• Selective for FGFR2b – expect superior therapeutic index

94


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


Charles Fuchs, MD, MPH

Landscape of Therapies in Advanced Gastric Cancer

Charles S. Fuchs, MDDana-Farber Cancer Institute

Harvard Medical SchoolBoston, MA

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 = 4th common malignancy

Second most common cause of cancer mortality

Gastric Cancer Mortality:Regional Differences

Jemal et al. CA Cancer J Clin. 2006. 56:106.

0

10

20

30

40

per 1

00,0

00 p

opul

atio

n

Uni

ted

Stat

es

Chi

le

Chi

na

Col

umbi

a

Japa

n

Pola

nd

Vene

zuel

a

Ger

man

y

Fran

ce

Hun

gary

Treatment of Metastatic Gastric Cancer

Approximately two thirds patients present with advanced stage disease1

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 regions1,2

Conventional chemotherapy has limited efficacy, with median survival of ~10 months3

Predictive biomarkers could refine treatment strategies3

HER: predictive biomarker for treatment with trastuzumab4

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):1657-1666;

3. Lim SM, et al. World J Gastroenterol. 2014;20(8):2042-50;4. Bang YJ, et al. Lancet. 2010;376(9742):687-97.

Phase III chemotherapy trials leading to current standard practice in advanced gastric cancer

1. Webb A, et al. J Clin Oncol. 1997;15(1):261–72. Van Cutsem E, et al. J Clin Oncol. 2006;24(32):4991-7

3. Koizumi W, et al. Lancet Oncol. 2008;9(3):215-21

Study Treatment (n) RR (95% CI) Median OS PFSTTP

(95% CI)

Webb et al1

FAMTX (108) 21% (13-29) 5.7 mo 3.4 mo n/a

ECF (111) 45% (36-54)(P=.0002)

8.9 mo(P=.0009)

7.4 mo(P=.00006) n/a

V3252

CF (224) 25% (19.9-31.7) 8.6 mo(95% Ci 7.2-9.5) n/a 3.7 mo

(3.4-4.5)

DCF (221) 37% (30.3-43.4)(P=.01)

9.2 mo(95% CI 8.4-10.6) n/a 5.6 mo

(4.9-5.9)

SPIRIT3

S-1 (150) n/a 11.0 mo(IQR 5.6-19.8)

4.0 mo(IQR 2.1-6.8) n/a

CDDP + S-1 (149) n/a 13.0 mo(IQR 7.6-21.9)

6.0 mo(IQR 3.3-12.9)

(P<0.0001)n/a

Developing Targeted Therapies in Gastric Cancer

ToGA: A Randomized, Open Label Multicenter Phase III Study

103

HER2-positive*advanced

gastric or GEJ cancer(n=584)

Capecitabine1 or iv 5-FU2†

+ cisplatin3

(n=290)

R

*IHC 3+ or FISH+5-FU=5-fluorouracil; GEJ=gastroesophageal junction; R=randomization; ECOG PS =Eastern Cooperative Oncology Group performance score.

Capecitabine or iv 5-FU2†

+ cisplatin3 + Herceptin(n=294)

3807 patients screened810 HER2-positive

(22.1%)

Bang YJ, et al. Lancet. 2010;376:687-697.

• Stratification factors• Advanced vs. metastatic disease• GC vs. GEJ• Measurable vs. non-measureable• ECOG PS 0-1 vs. 2• Capecitabine vs. 5-FU

†Chosen at investigator’s discretion1 1000 mg/m2 bid d1-14 q3w x 6 cycles2 800 mg/m2/day continuous iv infusion d1-5 q3w x 6 cycles3 80 mg/m2 q3w x 6 cycles4 8 mg/kg loading dose followed by 6 mg/kg q3w until disease progression

ToGA Primary Endpoint: Overall Survival

104Bang YJ, et al. Lancet. 2010;376:687-697.

EventsMedian

OS (mo)

HR 95% CI p-value

FC + Herceptin 167 13.8 0.74 0.60,

0.91 0.0046

FC 182 11.1

Time (months)

11.1 13.8

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 360.00.10.20.30.40.50.60.70.80.91.0

Prob

abili

ty

294290

277266

246223

209185

173143

147117

11390

9064

7147

5632

4324

3016

2114

137

126

65

40

10

00

No. at risk

F+C+HerceptinF+C

F=fluoropyrimidine (either fluorouracil or capecitabine); C=cisplatin.

AngiogenesisTumor growth

VEGF-A

VEGFR2

VEGF-A

VEGFR2

Ligand binding activates VEGFR2 andp44/p42 MAP kinases

Ramucirumab

No signaling

Inhibit new blood vesselformation and tumor growth

Ramucirumab binds to VEGFR2, blocks VEGFligand binding

VEGF binds toVEGFR2 receptor;VEGF-C, -D competefor binding toVEGFR2

♦ 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.

Role of VEGF Pathway in Tumor Growth

Endothelial cell membrane

VEGF-CVEGF-D

VEGF-CVEGF-D

Ramucirumab 8 mg/kg q2wk

+ BSC (n = 238)

RANDOMIZE

Placebo q2wk +

BSC (n = 117)

SCREEN

Treatment until disease progression

or intolerable

toxicity

Tumor assessment,

survival, and safety follow-up

N = 355• 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

REGARD Study Design

2:1

Abbreviations: BSC=best supportive care; GEJ= gastroesophageal junction Fuchs et al. Lancet 2013

Months

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 26 27 28

Ove

rall

Surv

ival

0.0

0.2

0.4

0.6

0.8

1.0

RamucirumabPlaceboCensoredCensored

Ram 238 154 92 49 17 7 3 0 0Plcb 117 66 34 20 7 4 2 1 0

No. at Risk

HR (95% CI) = 0.776 (0.603, 0.998)Log rank P-value (stratified) = 0.0473

Ramucirumab PlaceboPatients / Events 238 / 179 117 / 99Median (mos) (95% CI)

5.2 (4.4, 5.7) 3.8 (2.8, 4.7)

6-month OS 42% 32%12-month OS 18% 11%

REGARD: Overall Survival

Fuchs et al. Lancet 2013

Treat until disease

progression or

intolerable toxicity

• Important inclusion criteria:- Metastatic or loc. adv. unresectable gastric or GEJ* adenocarcinoma- Progression after 1st line platinum/fluoropyrimidine based chemotherapy

• Stratification factors:- Geographic region, - Measurable vs non-measurable disease, - Time to progression on 1st line therapy (< 6 mos vs. ≥ 6 mos)

Ramucirumab 8 mg/kg day 1&15+ Paclitaxel 80 mg/m2 day 1,8 &15

of a 28-day cycleN = 330

Placebo day 1&15 + Paclitaxel 80 mg/m2 day 1,8 &15

N = 335

SCREEN

RANDOMIZE

Survival and safety

follow-up

RAINBOW: Study Design

* GEJ= gastroesophageal junction; gastric and GEJ will be summarized under the term GC

1:1

RAINBOW: Overall Survival

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Ove

rall

Sur

viva

l Pro

babi

lity

Months

RAM+PTX

PBO+PTX

HR (95% CI) = 0.807 (0.678, 0.962)Stratified log rank p-value = 0.0169

RAM + PTX PBO + PTXPatients / Events 330 / 256 335 / 260Median(mos) (95% CI) 9.63 (8.48, 10.81) 7.36 (6.31, 8.38)

6-month OS 72% 57%12-month OS 40% 30%

RAM + PTX 330 308 267 228 185 148 116 78 60 41 24 13 6 1 0PBO + PTX 335 294 241 180 143 109 81 64 47 30 22 13 5 2 0

No. at risk

Censored

Δ mOS = 2.3 months

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

Smollen et al PNAS, 2006

Yapp et al J Clin Onc 2011:

Phase I trial of ARQ197

Minor regression in gastric cancer

RILOMET-1: Phase III trial of ECX +/- rilotumumab in MET-positive gastroesophageal adenocarcinoma

ECX + rilotumumab

ECX + placebo

Primary endpoint:overall survival

450 pts (estimated enrollment) with MET+ GE adenocarcinoma

RANDOMIZE Result:

No benefit for Rilotumumab

Randomized Trial of Onartuzumab in Advanced Gastric Cancer

• 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/m2 + leucovorin 200 mg/m2 + 5-fluorouracil 400 mg/m2 bolus and 2400 mg/m2 iv

Eligibility criteria• Age >18

• Metastatic GEC• HER2 negative• ECOG PS 0/1

• No prior therapy for metastatic disease• Tissue available

N=123

mFOLFOX6* + onartuzumab

(10 mg/kg) q2wN=62

mFOLFOX6* + placebo

q2wN=61

R

1:1

12 cycles

Onartuzumab PD

Placebo PD

Presented by: Manish Shah

Primary endpoint: PFS

• The stratified HR for PFS in the MET-negative population was 0.99 (95% CI 0.59–1.68)

*50% staining cut-off; CI, confidence interval

ITT MET-positive*

PFS

prob

abilit

y (%

)

Median PFS6.77 vs 6.97

Stratified HR 1.06 (95% CI 0.71–1.63)

p=0.7149

100

80

60

40

20

0

0 1 2 3 4 5 6 7 8 9 10 1112 13 1415 16

Placebo + mFOLFOX6 (N=61)Onartuzumab + mFOLFOX6 (N=62)Censored

Time (months)

PFS

prob

abilit

y (%

)

Median PFS5.95 vs 6.8

Stratified HR 1.38(95% CI 0.60–3.20)

p=0.4514

100

80

60

40

20

0

0 1 2 3 4 5 6 7 8 9 10 1112 13 1415 16

Placebo + mFOLFOX6 (N=19)Onartuzumab + mFOLFOX6 (N=16)Censored

Time (months) No of patients at riskPlacebo + mFOLFOX6Onartuzumab + mFOLFOX6

1916

1914

1413

1310

1110

109

106

84

64

53

51

31

1No of patients at riskPlacebo + mFOLFOX6Onartuzumab + mFOLFOX6

6162

5058

5353

5249

4848

4440

3931

2924

2421

1814

1110

63

52

11

1

Presented by: Manish Shah

114

AMG337: Responses in Patients With MET-Amplified GEJ/Gastric/Esophageal Cancer

• 13 patients with MET-amplified GEJ/gastric/ esophageal cancer treated to date; ORR = 8/13 (62%)

%∆

SOD

Fro

m B

asel

ine

-100%

-80%

-60%

-40%

-20%

0%

20%

40%

60%

80%

PR per RECIST 1.1

4wk+21wk

4wk17wk

9wk17wk

4wk29wk

4wk25wk

4wk+96wk

4wk+155wk

aLocal read as of Dec 8, 2014. bLocal read as of Sept 10, 2014.Central read as of Sept 18, 2014 for all other patients.One patient not shown with non-target lesions had clinical progression.

b

4wk+9wk

a

On active treatment Off treatment

Time to response:On treatment:

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

Distinct Pattern of Focal Amplifications Between Upper/Lower GI Adenocarcinomas

Dulak, Schumacher et al Cancer Research 2012

High-Level Amplifications

Significant amplifications (across all gut adenocarcinomas)Cytoband Residual q-value Peak Boundaries

(Mb)

Number of Genes in

Peak

Candidate Target(s) (Bold designates therapeutic target)

Gut Adenocarcinoma Types Represented

Gut Adenocarcinomas12p12.1 8.04E-51 25.23-25.34 3 KRAS E, G18q11.2 5.05E-37 17.95-18.05 1 GATA6 E, G, C17q12 4.34E-35 34.97-35.27 10 ERBB2 E, G, C19q12 5.97E-34 34.95-35.10 1 CCNE1 E, G

8q24.21 8.23E-34 128.50-128.83 2 MYC E, G, C8p23.1 2.10E-32 11.41-11.71 4 GATA4 E, G

11q13.2 5.26E-22 68.97-69.49 5CCND1, FGF3, FGF4,

FGF19 E, G7q21.2 3.36E-17 92.32-92.50 1 CDK6* E6p21.1 2.12E-16 43.79-43.99 2 VEGFA E, G7p11.2 6.71E-16 54.92-55.28 1 EGFR E, G

17q21.2 2.23E-11 37.02-37.21 7 E9p13.3 7.03E-09 35.52-35.93 24 E12q15 6.23E-08 67-09-68.25 10 MDM2, FRS2 E, G7q22.1 1.41E-07 98.41-99.02 16 E13q13.1 2.04E-06 32.18-33.33 4 E10q22.2 1.10E-05 75.00-75.80 16 E7q31.2 1.32E-05 115.98-116.42 6 MET E1q21.3 1.69E-05 146.23-150.89 106 MCL1 E1q42.3 1.71E-04 233.02-233.42 4 G

10q26.12 3.17E-04 122.75-123.37 1 FGFR2 E13q14.11 3.67E-04 40.27-40.83 10 E

Statistical analysis of focal amplifications across gut adenocarcinomas

BOLD= potential target5/4/2015

Molecular Subtypes of GC and Key Features

Ryo Sakai

CIN Tumors: Highly Recurrent Amplification of Oncogenes

Nils Wilheim

FGFR2 Gene Amplification and ClinicopathologicalFeatures in Gastric Cancer

British Journal of Cancer (2012) 106, 727–732

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

• 3/13 patients had retinal pigment epithelial detachment that led to dose interruptions or discontinuation

• Study did not meet pre-specified efficacy endpoint for continuation

Arkenau et al. Proc ASCO 2014

Novel Targets for Gastric Cancer: 2015

Target Progress to date

HER2MoAb demonstrates efficacy (Trastuzumab);

TKIs not proven beneficial; other strategies under development (TDM1; pertuzumab)

VEGF, VEGFR2 Ramucirumab approved in 2014

MET Trials based on IHC failed; preliminary data based on amplification suggest activity

PDL1 Preliminary signal for PD-1 MoAb; trials ongoing

FGFR2 Initial efforts for TKIs not demonstrating convincing benefit; studies of MoAb ongoing


Immuno-Oncology Novel Drug Discovery

Brian Wong, MD, PhDVP of Research & Head of Immuno-Oncology


Immuno-Oncology Is Transforming Cancer Treatment but Significant Opportunity Remains

Consensus from KoLs: field is just “scratching the surface”

Indication ORR Source

Melanoma 32% CheckMate-037

SqNSCLC 15% CheckMate-063

RCC 29% JCO 2015

Ovarian 17% ASCO 2014

CRC 0% NEJM 2012

Opdivo (nivolumab) response rates

127


Many New IO Targets Remain to be Discovered in the Tumor Microenvironment

Cell Surface Proteins Regulate Immune Responses to the Tumor

T Cell

Tumor Cell

Macrophage

128


Our Vision: Develop New Therapies with a Global Understanding of Tumor Immunity

Find All Tumor Immune RegulatorsAnd Their Binding Partners

Define Which Immune Regulators Operate in Which Tumors

Use this proprietary “map” to develop the best therapeutics for a defined patient population

Imm

unom

eG

enes

Cancer 1 Cancer 2 Cancer 4C3

Inactive T Cell

Tumor Cell

T Cell

Tumor Cell

Macrophage

FP Novel

FP Novel

FP NovelFP Novel

FP Novel

FP Novel FP Novel

FP Novel

129


Our Platforms Comprehensively Test All Cell Surface Proteins in the Tumor Microenvironment as Targets

Antibody Targets

• Novel Checkpoints

• Novel Immune Activators

Proprietary Screens

Cell-basedScreens

In vivo Screens


FPRX Immunome

LibraryContains substantially all cell surface proteins that regulate the tumor micro-environment

• Systematic & unbiased selection of the best functional immunome targets• Goal: 1 IND per year starting in 2017

Immunome*:500 Proteins

*Proteins with motifs characteristic of checkpoints and immune regulators

130


Cell-Based Screening Led to A Novel Potent Regulator of Macrophages

Proprietary Screens

Cell-basedScreens

In vivo Screens


IL-34

Positive Control

FivePrime protein library

Known cytokines active

Effe

ct o

n M

onoc

yte

Pro

lifer

atio

n

IL-34, A Master Regulator of Monocytes and Macrophage

We identified CSF1R as the receptor for IL-34

131


We Are Screening for Novel Regulators of Immune Cells in the Tumor Microenvironment

• Macrophage (TAMs)• FPA008 was developed based

on our discovery of IL-34

• Effector T cells• Find novel inhibitors

(checkpoints) and block them with antibodies

• Regulatory T cells

• MDSC

• Dendritic Cells

Inactive T Cell

Tumor Cell

T Cell

Tumor Cell

Macrophage

132


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 immunomefor novel T cell checkpoints

• Example: Novel T Cell Checkpoint 1 shows similar or better potency to PDL1 in inhibiting T cells:

133


Novel T Cell Checkpoint 1 is Selectively Expressed on Effector CD4+ T Cells and Tregs

Memory CD4 T cells

Tregs

Expression on the same T cell subsets is observed in tumors

Relative RNA Expression Across a Panel of Tissues and Immune Subsets

134


Results consistent with the ability of T Cell Checkpoint 1 to suppress T cell activation

T Cell Checkpoint 1 is a Potential Antibody Target

Novel Checkpoint 1Control

Soluble Checkpoint 1 enhances tumor growth in an in vivo colon cancer model

135


An Antibody Blocking T Cell Checkpoint 1 EnhancesT Cell Activation

T Cell Interferon-γ production assay

Checkpoint 1 Antibody

IsotypeControl

Inte

rfero

n-γ

Pro

duce

d (B

ackg

roun

d su

btra

cted

)

We are generating fully human antibodies to T Cell Checkpoint 1

136


In Vivo Screening of the Entire Immunome for Regulators of the Tumor Microenvironment

Proprietary Screens

Cell-basedScreens

In vivo Screens


Syngeneic Tumor Model

Measure tumor volume

• In vivo screens better model the tumor microenvironment

• Rapid in vivo expression of extracellular proteins bypasses protein scale up, purification, and formulation

Expressed proteins

Inject vector expressing Immunomelibrary member

137

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://www.vectorportal.com/subcategory/168/SYRINGE-VECTOR-CLIP-ART.eps/ifile/14151/detailtest.asp&ei=-bo6VZb_IMeJoQTN34DYBg&bvm=bv.91665533,d.cGU&psig=AFQjCNEwn-JmRYtMBYSnhGx12ikBXX4wvw&ust=1429998648006925

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://www.vectorportal.com/subcategory/168/SYRINGE-VECTOR-CLIP-ART.eps/ifile/14151/detailtest.asp&ei=-bo6VZb_IMeJoQTN34DYBg&bvm=bv.91665533,d.cGU&psig=AFQjCNEwn-JmRYtMBYSnhGx12ikBXX4wvw&ust=1429998648006925


Potential Immunome Hits Identified In an Ongoing In Vivo Tumor Screen

Incr

ease

dTu

mor

Gro

wth

Dec

reas

edTu

mor

Gro

wth

Potential agonist hits

Potential checkpoint hits

150 of 500 immunome proteins tested to date

138


Identification of Ligands for Orphan Checkpoints Leads to New Targets and Enables Antibody Development

Proprietary Screens


• 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

Cell-basedScreens

In vivo Screens

139


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


Expectations



FP-1039FGF ligand trap

Immuno-Oncology Research

Gastric Cancer Initial data from solid tumor & unselected gastric cancer patients by end of 2015

Squamous NSCLC & Mesothelioma

GSK to present preliminary efficacy data by end of 2015

Cancer Advance internal drug candidates to preclinical development

INDICATION STATUSPROGRAM

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

141


Q&A


Research & Development Day

May 5, 2015The Chatwal Hotel, New York

research & development day€¦ · the advancement of our immuno- oncology program; and (vi)...

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