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

Transcription

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

2 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

3 Bayer s Clinical Antibody Conjugate Pipeline Antibody-Drug Conjugates - ADCs Anetumab ravtansine: Mesothelin-DM4, to enter into Phase 2 BAY , C4.4a-ADC novel auristatin, Phase 1 dose escalation ongoing BAY , 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

4 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

5 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 Page 5 6 th ADC Summit San Diego, 2015

6 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

7 BAY binds to all described splice variants of FGFR2 BAY : 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 Binding of BAY to human N-terminal FGFR2 peptides (Biacore) Time K D = 75 nm ka (1/Ms) = 1.49 E +06 kd (1/s) = Rmax (RU) = Peptide and alanine scan-based epitope mapping 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

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

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

10 Characteristics of BAY Mode-of-Action: microtubule destabilization 3.5x10 5 Pure, homogeneous preparation DAR ~3.8 DAR x10 5 tr = min Mw 146 kda 99.8 % (UV) x x10 5 molar mass (g/mol) 1.5x UV absorbance 1.0x10 5 SEC-MALS 5.0x10 4 tr = min 0.2 % (UV) time (min) Drug-to-antibody ratio from LC-MS Page 10 6 th ADC Summit San Diego, 2015

11 BAY inhibits proliferation of FGFR2 positive cells potently and selectively in vitro Cell Line Indication IC50 BAY [mol/l] KatoIII Gastric Ca SUM-52PE TNBC NCI-H716 CRC MFM-223 TNBC SNU-16 Gastric Ca KYSE-180 Esoph. Ca T1 TNBC FACS QuantiBrite : quantitative FACS analysis with BAY phycoerythrin (PE) 1:1 In vitro potency of BAY in cancer cells with FGFR2 Abs bound per cell MDA-MB-231 TNBC High potency & selectivity of BAY 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

12 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 (5 mg/kg, i.v., SD) Page 12 6 th ADC Summit San Diego, 2015

13 BAY : dose-dependent & selective inhibition of SNU-16 gastric cancer model in vivo Tumor volume on day 32 [mm 3 ] [mg/kg] Vehicle Q4Dx3 Q10Dx3 Q4Dx3 * * * * Q4Dx3 DAR1.8 DAR4.5 DAR Q10Dx3 Tum or volum e [m ean ± SD, m m 3 ] **, p < 0.01; ***, p < ** *** *** *** Time after tumor cell inoculation [days] Vehicle BAY control-adc BAY , 5 mg/kg, DAR 1.8, Q4Dx3 BAY , 5 mg/kg, DAR 1.8, Q10Dx3 BAY , 5 mg/kg, DAR 4.5, Q4Dx3 Q10Dx3 Q7Dx3 BAY , 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

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

15 BAY 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 ] Tim e after first treatm ent [days] * * Vehicle BAY , 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

16 BAY Complete Responses & high selectivity in MFM-223 model Tumor volume Waterfall plot 340 Vehicle **, p < 0.01; ***, p < BAY , 1 mg/kg, Q7Dx3 Tum or volum e [m ean ± SD, m m 3 ] BAY , 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 Time after tumor cell inoculation [days] MFM-223 is a TNBC model with FGFR2 amplification and RNA/ protein overexpression ** *** *** Final tumor weight [mg] [mg/kg] Vehicle Control-ADC * * * BAY control-adc Doxorubicin Page 16 6 th ADC Summit San Diego, 2015

17 BAY 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 ] BAY , 7.5 mg/kg, Q7Dx3 control-adc, 7.5 mg/kg, Q7Dx3 V inorelbine, 10 m g/kg, Q 7D x3 *** *** FGFR2, RNAscope, 40x 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

18 BAY in vivo efficacy in ovarian cancer Ov A PDX model FISH: FGFR2 *, p < 0.05 ; ***, p < 0.001; Q7Dx3 OV A 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

19 BAY 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 Secondary objectives Evaluate the pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, biomarkers, and tumor response profile of BAY Study is ongoing: NCT Page 19 6 th ADC Summit San Diego, 2015

20 BAY Summary BAY : potent and selective FGFR2-targeting ADC BAY 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 induces tumor regressions (CRs and PRs) in FGFR2 positive TNBC and gastric cancer xenograft models in mice in monotherapy BAY is well tolerated A Phase I study with BAY is recruiting (NCT ) Page 20 6 th ADC Summit San Diego, 2015