Bicycle Therapeutics Plc · NASDAQ:BCYC
Bicycle Therapeutics — AACR Annual Meeting 2019
11 slides from Bicycle Therapeutics's conference presentation, 2019
Slide 1: BT5528, an EphA2-targeting Bicycle Toxin Conjugate (BTC)
BT5528, an EphA2-targeting Bicycle® Toxin Conjugate (BTC): Profound efficacy without bleeding and coagulation abnormalities in animal models Gavin Bennett AACR Annual Meeting 2019 Atlanta 4481
Slide 2: Bicycles: a new therapeutic modality
Bicycles®: a new therapeutic modality Linear peptide Bicycle Scaffold X Loop Loop COOH 1 2 NH2 Chemical NH2 COOH modification with scaffold Highly constrained: high affinity, exquisite selectivity, excellent stability Large binding footprint: disrupt protein-protein interactions Fully synthetic: NCE
Slide 3: EphA2: Biological rationale
EphA2: Biological rationale Benign Breast • Erythropoietin-producing hepatocellular A2 receptor: member of Eph subfamily of receptor tyrosine kinases • Regulates cell migration, adhesion proliferation and differentiation • Overexpression in human cancers, correlates with tumour progression Invasive
Slide 4: BT5528: structure & profile
BT5528: structure & profile High affinity binding to EphA2 protein across species BT5528(1μM) Ligand-binding %identity to Binding affinity (SPR, using & on cells. Species cross-reactivity, high selectivity. domain hEphA2 BT5528, KD nM) Human Human EphA1 54 > @ 5uM BT5528 affinity Human Mouse Rat NHP
Slide 5: BT5528 delivers MMAE to tumour
BT5528 delivers MMAE to tumour 1000 Tumour MMAE Plasma MMAE Single dose of BT5528 Analyte (pmol/g) Plasma BT5528 • Produces high MMAE 100 concentrations in tumour • Stable from 2h to >48h 10 • Transient exposure of both BT5528 & MMAE PC3 tumour xenograft in plasma • High EphA2 1 0 12 24 36 48 Time a
Slide 6: BT5528 induces mitotic arrest in tumour
BT5528 induces mitotic arrest in tumour 25 Single dose of BT5528 • Produces high MMAE 20 % pHH3+ nuclei concentrations in tumour • Stable from 2h to >48h 15 • Transient exposure of 10 both BT5528 & MMAE Tumour pHH3 in plasma 5 • Induces mitotic arrest PC3 tumour xenograft • High EphA2 • Measurable b
Slide 7: BT5528 produces tumour regression
BT5528 produces tumour regression Weekly dosing of BT5528 500 Tumour Volume (%D0) • Produces high MMAE concentrations in tumour 400 • Stable from 2h to >48h 300 Vehicle i.v qw • Transient exposure of 200 BT5528 0.5mg/kg both BT5528 & MMAE in plasma 100 • Induces mitotic arrest • Measurable by pHH3 0
Slide 8: Efficacy: target-mediated, flexible dosing
BT5528 efficacy: target-mediated, flexible dosing 800 (% of baseline, minimum, D14-28) MOLP-8 EphA2 expression • BT5528 shows target-dependent 400 200 efficacy Efficacy OE-21 Tumour volume • Significant regression in a wide range of 150 Tumour Growth EphA2-positive tumours Lu-01-0486 Lu-01-0412 SK-O
Slide 9: Differentiation from ADC in complex PDX models
BT5528: differentiation from ADC in complex PDX models Bicycle distribution at 4000 4000 60 min Vehicle i.v qw Vehicle, qw BT5528 3mg/kg BT5528 3mg/kg ADC 3mg/kg ADC 3mg/kg 3000 Moderate EphA2 3000 High EphA2 Tumour Volume (mm3) Tumour Volume (mm3) expression expression 2000 2000 ADC distribution at
Slide 10: Differentiation from ADC in bleeding/coagulation & liver toxicology
BT5528: differentiation from ADC in bleeding/ coagulation & liver toxicology Findings from MEDI-547 Phase I study Treatment related adverse events # events (% of patients) n of total ALT increased 3 (50) 3/6 Bleeding observed on days 3-8 Haemorrhage 6 (83.3) 5/6 following a single dose of MEDI-547 1
Slide 11: BT5528: a Bicycle Toxin Conjugate targeting EphA2 for the Treatment of Solid Tumours
BT5528: a Bicycle Toxin Conjugate targeting EphA2 for the Treatment of Solid Tumours • EphA2 is highly expressed on tumour cell surface in a wide range of solid tumours • BT5528 was developed as a BTC to target EphA2 • High affinity binding • Short half-life and renal elimination • “Hit and run” del