BAY 1187982, a novel ADC with potent anti-tumor activity, targeting all isoforms of FGFR2

BAY 1187982, a novel ADC with potent anti-tumor activity, targeting all isoforms of FGFR2 6 th World ADC, San Diego, October 20, 2015 Anette Sommer

Disclosure Information I have the following financial relationships to disclose: I am an employee of BAYER AG I hold shares of BAYER AG I will not discuss off-label use and / or investigational use in my presentation Page 2 6 th ADC Summit San Diego, 2015

Bayer s Clinical Antibody Conjugate Pipeline Antibody-Drug Conjugates - ADCs Anetumab ravtansine: Mesothelin-DM4, to enter into Phase 2 BAY 1129980, C4.4a-ADC novel auristatin, Phase 1 dose escalation ongoing BAY 1187982, FGFR2-ADC novel auristatin, Phase 1 dose escalation ongoing Targeted Thorium Conjugates - TTCs See also presentation by Urs Hagemann on Oct. 21 Page 3 6 th ADC Summit San Diego, 2015

FGFR2 Fibroblast Growth Factor Receptor 2 FGFR2 is a transmembrane receptor tyrosine kinase FGFR2 signaling is involved several biological processes during Embryonic development Tissue homeostasis e.g. Cell proliferation Survival Differentiation Migration Low level of expression in normal human tissues and organs Page 4 6 th ADC Summit San Diego, 2015

Isoforms of FGFR2 in the Extracellular Domain (ECD) Alternative splicing in the IgG domains results in FGFR2 isoforms with different ligand binding & expression pattern Deletion of D1 in FGFR2 alpha isoform FGFR2 beta isoform Splicing within D3 IIIb (exons 7+8) IIIc (exons 7+9) A short sequence is contained in all 4 isoforms Binding epitope of BAY 1179470 Page 5 6 th ADC Summit San Diego, 2015

FGFR2 Alterations in Cancer Protein/ RNA overexpression, eg. in gastric and breast cancer DNA amplification, eg. in gastric cancer and TNBC Associated with poor outcome, eg. of gastric Ca patients Constitutively active FGFR2 fusion proteins, eg. in cholangiocarcinoma, breast cancer, ovarian cancer Activating mutations, eg. in endometrial cancer Overexpression and amplification of FGFR2 in various solid cancer indications renders FGFR2 an interesting target for an ADC approach Page 6 6 th ADC Summit San Diego, 2015

BAY 1179470 binds to all described splice variants of FGFR2 BAY 1179470: fully human IgG1 derived from the BioInvent n-coder library Binds to epitope at extreme N-terminus of FGFR2 Epitope is present in all described FGFR2 splice variants Epitope is 100% identical in human, monkey, rat, and murine FGFR2 Fully cross-reactive to orthologs of FGFR2 in human, monkey, rat, and mouse Response 30 25 20 15 10 5 0 Binding of BAY 1179470 to human N-terminal FGFR2 peptides (Biacore) -5-50 0 50 100 150 200 Time K D = 75 nm ka (1/Ms) = 1.49 E +06 kd (1/s) = 0.1118 Rmax (RU) = 33.31 Peptide and alanine scan-based epitope mapping -6-5 -4-3 -2-1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 A T L S L A R P S F S L V E D T T L E P E 250 Signal peptide Page 7 6 th ADC Summit San Diego, 2015

FGFR2 Ab BAY 1179470 Induces Internalization of FGFR2 SUM-52PE BAY 1179470 Rab7 lysosome M6PR late endosome 6h BAY 1179470 induced receptor internalization correlates with FGFR2 FACS levels Co-localization of BAY 1179470 with Rab7 indicates that most of the internalized antibody follows the lysosomal pathway Page 8 6 th ADC Summit San Diego, 2015

FGFR2-ADC BAY 1187982 BAY 1187982 is an antibody-drug conjugate directed against FGFR2 Two activities in one molecule Targeting of FGFR2 positive tumors with the FGFR2 Ab BAY 1179470 Delivery of a highly cytotoxic payload of the auristatin class*) *) technology licensed from Seattle Genetics Page 9 6 th ADC Summit San Diego, 2015

Characteristics of BAY 1187982 Mode-of-Action: microtubule destabilization 3.5x10 5 Pure, homogeneous preparation DAR ~3.8 DAR 3.8 3.0x10 5 tr = 24.41 min Mw 146 kda 99.8 % (UV) 1.0 2.5x10 5 0.8 2.0x10 5 molar mass (g/mol) 1.5x10 5 0.6 0.4 UV absorbance 1.0x10 5 SEC-MALS 5.0x10 4 tr = 20.50 min 0.2 % (UV) 0.0 0.0 10.0 20.0 30.0 40.0 50.0 time (min) 0.2 0.0 Drug-to-antibody ratio from LC-MS Page 10 6 th ADC Summit San Diego, 2015

BAY 1187982 inhibits proliferation of FGFR2 positive cells potently and selectively in vitro Cell Line Indication IC50 BAY 1187982 [mol/l] KatoIII Gastric Ca 8.3 10-10 SUM-52PE TNBC 9.7 10-11 NCI-H716 CRC 3.7 10-10 MFM-223 TNBC 5.8 10-10 SNU-16 Gastric Ca 4.3 10-10 KYSE-180 Esoph. Ca 4.1 10-8 4T1 TNBC 2.5 10-7 FACS QuantiBrite : quantitative FACS analysis with BAY 1179470-phycoerythrin (PE) 1:1 In vitro potency of BAY 1187982 in cancer cells with 11.000 FGFR2 Abs bound per cell MDA-MB-231 TNBC 2.5 10-7 High potency & selectivity of BAY 1187982 in vitro Potency in the subnanomolar range >100-fold selective vs. FGFR2-negative cell lines & control ADC Page 11 6 th ADC Summit San Diego, 2015

More than 30-fold enrichment of toxophore metabolite in FGFR2 positive NCI-H716 tumors in vivo Treatment of FGFR2 positive NCI-H716 tumor-bearing female NMRI nu/nu mice with BAY 1187982 (5 mg/kg, i.v., SD) Page 12 6 th ADC Summit San Diego, 2015

BAY 1187982: dose-dependent & selective inhibition of SNU-16 gastric cancer model in vivo Tumor volume on day 32 [mm 3 ] 800 600 400 200 0 [mg/kg] Vehicle Q4Dx3 Q10Dx3 Q4Dx3 * * * * Q4Dx3 DAR1.8 DAR4.5 DAR4.7 5 1 0.5 5 5 1 0.5 5 5 1 5 Q10Dx3 Tum or volum e [m ean ± SD, m m 3 ] 600 500 400 300 200 100 0 **, p < 0.01; ***, p < 0.001 ** *** *** *** 10 20 30 40 50 60 70 Time after tumor cell inoculation [days] Vehicle BAY 1187982 control-adc BAY 1187982, 5 mg/kg, DAR 1.8, Q4Dx3 BAY 1187982, 5 mg/kg, DAR 1.8, Q10Dx3 BAY 1187982, 5 mg/kg, DAR 4.5, Q4Dx3 Q10Dx3 Q7Dx3 BAY 1187982, 5 mg/kg, DAR 4.5, Q10Dx3 control-adc, 5 mg/kg, DAR 4.7, Q4Dx3 control-a D C, 5 m g/kg, D A R 4.7, Q 10D x3 Page 13 6 th ADC Summit San Diego, 2015

BAY 1187982: high in vivo efficacy in SNU-16 gastric cancer model and well tolerated in mice Tumor weight Body weight *, p < 0.05. MED in SNU-16: 1.25 mg/kg at Q7Dx3 with a T/C of 0.24 (day 36) BAY 1187982 was well tolerated, only 10 mg/kg reversibly affecting body weight Page 14 6 th ADC Summit San Diego, 2015

BAY 1187982 - Complete Responses in GA0033 gastric cancer PDX model 1500 GA0033 Tumor volume FGFR2, RNAscope, 40x Tum or volum e [m ean ± SD, m m 3 ] 1000 500 0 0 5 10 15 20 Tim e after first treatm ent [days] * * Vehicle BAY 1187982, 7.5 mg/kg, Q7Dx3 control-adc, 7.5 mg/kg, Q7Dx3 V inorelbine, 10 m g/kg, Q 7D x3 *, p < 0.05; n=5 GA0033 is a PDX model derived from a gastric cancer with high level of FGFR2 amplification and RNA and protein overexpression Page 15 6 th ADC Summit San Diego, 2015

BAY 1187982 - Complete Responses & high selectivity in MFM-223 model Tumor volume Waterfall plot 340 Vehicle **, p < 0.01; ***, p < 0.001 BAY 1187982, 1 mg/kg, Q7Dx3 Tum or volum e [m ean ± SD, m m 3 ] 280 220 160 100 40 BAY 1187982, 5 mg/kg, Q7Dx3 contro l-a D C, 1 m g/kg, Q 7D x3 contro l-a D C, 5 m g/kg, Q 7D x3 Doxorubicin, 10 mg/kg, Q14D -20 10 15 20 25 30 35 40 45 50 55 Time after tumor cell inoculation [days] MFM-223 is a TNBC model with FGFR2 amplification and RNA/ protein overexpression ** *** *** Final tumor weight [mg] 400 300 200 100 0 [mg/kg] Vehicle Control-ADC * * * 1 5 1 5 10 BAY 1187982 control-adc Doxorubicin Page 16 6 th ADC Summit San Diego, 2015

BAY 1187982 - high in vivo efficacy in BR1115 breast cancer PDX model 1500 Vehicle BR1115 ***, p < 0.001, n=5 FISH: FGFR2 / CEN10 Tum or volum e [m ean ± SD, m m 3 ] 1000 500 BAY 1187982, 7.5 mg/kg, Q7Dx3 control-adc, 7.5 mg/kg, Q7Dx3 V inorelbine, 10 m g/kg, Q 7D x3 *** *** FGFR2, RNAscope, 40x 0 0 5 10 15 20 Tim e after first treatm ent [days] BR1115 is a PDX model derived from a breast cancer with high level of FGFR2 amplification, RNA overexpression, and an FGFR2-GAB2 fusion gene Page 17 6 th ADC Summit San Diego, 2015

BAY 1187982 - in vivo efficacy in ovarian cancer Ov30-0511A PDX model FISH: FGFR2 *, p < 0.05 ; ***, p < 0.001; Q7Dx3 OV30-0511A is a PDX model derived from a mucinous type ovarian cancer with high level of FGFR2 amplification, RNA and protein overexpression Page 18 6 th ADC Summit San Diego, 2015

BAY 1187982 - Phase I Study Stage 1 Starting dose: based on preclinical toxicology data Cohort size n=3 Dose escalation following pre-defined dose levels guided by preclinical TK/TD and PK/PD evaluation Until at least 1 DLT or 2 drug-related AEs Grade 2 Stage 2 Consider all available safety data Perform dose-response modeling of DLT rates to identify MTD Select next dose adaptively (possibly close to MTD**) Final decision on next dose between investigator and sponsor C R M **DLT rate <20% Primary objectives Determine the safety, tolerability, and maximum tolerated dose (MTD) of BAY 1187982 Secondary objectives Evaluate the pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, biomarkers, and tumor response profile of BAY 1187982 Study is ongoing: NCT02368951 Page 19 6 th ADC Summit San Diego, 2015

BAY 1187982 Summary BAY 1187982: potent and selective FGFR2-targeting ADC BAY 1179470 Ab binds to all FGFR2 ECD isoforms Novel linker toxophore of the auristatin class The toxophore metabolite is enriched more than 30-fold in FGFR2 positive xenograft tumors compared to murine organs BAY 1187982 induces tumor regressions (CRs and PRs) in FGFR2 positive TNBC and gastric cancer xenograft models in mice in monotherapy BAY 1187982 is well tolerated A Phase I study with BAY 1187982 is recruiting (NCT02368951) Page 20 6 th ADC Summit San Diego, 2015