Captor Therapeutics Sa · GPW:CTX
Captor Therapeutics Sa — Investor Day (May 2022)
37 slides from Captor Therapeutics Sa's investor day presentation, May 18, 2022
Slide 1: Research & Development Day
Research & Development Day The Power of Targeted Protein Degradation (TPD) and How It Could Redefine the Hepatocellular Carcinoma (HCC) Therapy Paradigm May 18th 2022
Slide 2: Legal notice
Legal notice This document and the information contained herein (unless otherwise indicated) have been prepared by Captor Therapeutics S.A. (the “Issuer”) solely for informational purposes. For this notice, the presentation that follows shall mean and include the slides that follow, the oral present
Slide 3: About Captor
About Captor Wroclaw, Poland Basel, Switzerland Based in Wroclaw (Poland) and Basel (Switzerland) Backed by private investment and non-dilutive public funds Significantly oversubscribed IPO in April 2021 Disruptive platform in TPD drug discovery Five drug programs in large potential markets ~97 FTEs
Slide 4: Captor's TPD Platform
Captor’s TPD Platform Michał Walczak, Ph.D. Co-founder Chief Scientific Officer Business Use Only | Do not use without written consent of Captor Therapeutics Inc. © 2022 4
Slide 5: Principle of targeted protein degradation
Principle of targeted protein degradation Business Use Only | Do not use without written consent of Captor Therapeutics Inc. © 2022 5
Slide 6: A totally different pharmacology
A totally different pharmacology A small molecule inhibits A degrader drug one target protein can degrade molecule at a time and multiple target only when it is bound to proteins one after it. another. active inhibited active degraded degraded to be degraded Business Use Only | Do not use without wr
Slide 7: A revolutionary approach
A revolutionary approach 20th century 1990s – 2020s 2020 - ? Targeted drugs Targeted Protein Degradation (inhibitors, antibodies) Benefits Benefits + Highly specific due to targeting + 5x more druggable targets compared + Fewer side effects to traditional drugs + Efficacious in some previously + Pot
Slide 8: Captor's Optigrade platform
Captor’s OptigradeTM platform Platform differentiation Molecular Glues • Lead compounds both in • Screening paradigm rationalized molecular glues and bifunctional to find new targets degraders • Library of proprietary CRBN- Molecular • Structure-based hit finding and based molecular glues Glue lead
Slide 9: Molecular glues and Cereblon degrome
Molecular glues and Cereblon degrome Molecular Glue ZnF Target Non-ZnF Target ZNF517 PLK kinases ZNF582 NIMA kinases ZNF653 PAK kinases CRBN Protein of IKZF1/3 GTPases Interest ZFP91 WD repeat IKZF2/4 Chaperones PATZ1 Phosphatases Sievers Q., Petzold G. et al. Science (2018) 362(6414) Molecular Glue
Slide 10: Molecular glue discovery engine
Molecular glue discovery engine Molecular Glue Extended positive degron Protein- Degron protein Protein sequence docking production analysis and testing Geometric AI Extended negative degron Data Augmentation Business Use Only | Do not use without written consent of Captor Therapeutics Inc. © 2022 1
Slide 11: Molecular glue toolbox
Molecular glue toolbox Molecular Glue Molecular Glue Library PoI CRBN PoI CRBN detection High throughput CRBN recruitment assay A unique library of molecular glues developed • Excellent drug-like properties • Multiplexed by proteins • Rapidly growing focused library developed by • Detection of weak
Slide 12: Beyond the Cereblon ZnF degrome
Beyond the Cereblon ZnF degrome Molecular Glue ZnF Target Non-ZnF Target ZNF517 PLK kinases ZNF582 NIMA kinases ZNF653 PAK kinases CRBN Protein of IKZF1/3 GTPases Interest ZFP91 WD repeat IKZF2/4 Chaperones PATZ1 Phosphatases Sievers Q., Petzold G. et al. Science (2018) 362(6414) Molecular Glue Busi
Slide 13: Bifunctional degrader discovery
Bifunctional degrader discovery Bifunctional Degraders Protein of Interest (PoI) ligand generation capabilities • Modern ligand discovery methods (SBDD and FBLD) PoI ligand • Biophysical screening • X-ray crystallography • CryoEM and NMR via established collaborations • Multiple libraries of compoun
Slide 14: Selective bifunctional degraders of MCL-1 protein
Selective bifunctional degraders of MCL-1 protein Bifunctional Degraders Vehicle CPT-2036 (150 mpk) 2 24 2 4 8 12 24 48 Time kDa [hours] 3 MCL-1 7 25 PARP FL 15 10 PARP CL 0 200 15 Casp 3 cl 50 3 Total protein Vinculin 7 (Ponceau S) *CC-122 – IKAROS degrader (Celgene) **CC-885 – GSPT1 degrader (Celg
Slide 15: Huge potential for degraders based on novel ligases
Huge potential for degraders based on novel ligases New Ligases • There are ~600 different E3 ubiquitin ligases • So far, ligands identified to only a small fraction of E3 ligases • All clinical-stage degraders based on CRBN (and single one on VHL) CRBN VHL Subfamilies E3 ubiquitin ligases, generate
Slide 16: Selection of Novel Ligases for Next Generations of Degraders
Selection of Novel Ligases for Next Generations of New Degraders Ligases Captor’s 3rd generation of degraders Tissue specific expression Role in diseases, e.g. cancer Captor’s 2nd generation of degraders rd Essentiality 3 Safety Production feasibility nd “Ligand-able” and crystallizable Assays avail
Slide 17: LiLis - ligands to novel E3 ligases
LiLis TM - ligands to novel E3 ligases New Ligases • Expertise in E3 ligases: ~100 ligases expressed • Ligase ligand generation for novel E3s with differentiated profiles • Ligands identified and crystal structures solved Essentiality in cancer • Prototype degraders for 2 new ligases with a new assa
Slide 18: Highly potent ligands identified for first two priority ligases
Highly potent ligands identified for first two priority New Ligases ligases • FBS identified several hits (50µM to 1 mM) • Cullin-based substrate receptor • Current best ligand at ~20 nM • Current best ligands at 400 nM • > 60 structures, many with < 2A resolution • > 10 X-ray structures with fragme
Slide 19: The Captor pipeline
The Captor pipeline # Indications Modality Discovery Preclinical* IND Filing FIH** FIH** Hepatocellular CT-01 carcinoma MG Autoimmunity CT-02 Hematological cancer MG 2023 Liquid & solid CT-03 tumors BID MCL-1 target Colorectal CT-04 cancer BID Autoimmunity CT-05 Solid tumors & BID other Partnered Pr
Slide 20: Drug candidates advancing towards the clinic
Drug candidates advancing towards the clinic Project: CT-01 Project: CT-03 Positioning: Unique degradation Positioning: First-in-class MCL-1 Molecular profile Bifunctional degrader Glue Main indication: hepatocellular Degraders Main indications: blood cancers carcinoma Secondary indication: solid tu
Slide 21: A Novel Approach to Hepatocellular Carcinoma (HCC) Therapy
A Novel Approach to Hepatocellular Carcinoma (HCC) Therapy Paweł Dobrzański, Ph.D. Biology Department Director Business Use Only | Do not use without written consent of Captor Therapeutics Inc. © 2022 21
Slide 22: Targeting HCC with Molecular Glues
Targeting HCC with Molecular Glues CPT-6281 Pomalidomide Lenalidomide Business Use Only | Do not use without written consent of Captor Therapeutics Inc. © 2022 22
Slide 23: CPT-5170 and CPT-6281 have a unique degradation profile
CPT-5170 and CPT-6281 have a unique degradation profile Proteins down-regulated in Potent degradation of GSPT1, SALL4 and of an response to CT-01 compounds undisclosed target treatment in Hep3B cells GSPT1 Log2Fold-change CPT-6281 (5μM) vs DMSO Hep3B cells, 24h treatment Business Use Only | Do not u
Slide 24: Degradation of CT-01 targets in Hep3B is Cereblon dependent
Degradation of CT-01 targets in Hep3B is Cereblon dependent + + + ̶ ̶ NT siRNA 10 nM kDa ̶ ̶ ̶ + + siCRBN 10 nM 150 Sall4A 100 75 Sall4B 50 β-actin 37 (loading control) 50 CRBN 150 Vinculin (loading control) Business Use Only | Do not use without written consent of Captor Therapeutics Inc. © 2022 24
Slide 25: Rationale for targeting SALL4 in HCC
Rationale for targeting SALL4 in HCC • SALL4 is a transcription factor which is silenced in the adult liver. It is re-expressed in a sub-group of hepatocellular carcinomas and in several other cancers • SALL4 interacts with the NuRD complex to repress PTEN gene expression and to activate the AKT pat
Slide 26: Rationale for targeting GSPT1 in HCC
Rationale for targeting GSPT1 in HCC GSPT1 (eRF3A) is a translation termination factor critical for the release of nascent polypeptides from ribosomes 1. The rapid and continuous proliferation of highly malignant cancers requires efficient protein synthesis 2. Translational adaptations are crucial c
Slide 27: CPT-5170 and CPT-6281 are more potent than CC-90009 in HCC cell lines
CPT-5170 and CPT-6281 are more potent than CC- 90009 in HCC cell lines JHH-7 125 Number of colonies as % of DMSO control 100 75 50 25 0 B 2 2 B 2 2 B 2 2 B 5 15 B 5 75 46 75 46 75 46 1 1 -2 -2 -2 S- S- S- S- S- S- C C C B A A A A A A A A A A A A 1 nM 10 nM 100 nM 1 nM 10 nM 100 nM 1 nM 10 nM 100 nM
Slide 28: Degradation of GSPT1 mediates ISR and apoptosis
Degradation of GSPT1 by CPT-5170 or CPT-6281 mediates ISR1 and apoptosis Hep3B WT Hep3B GSPT1 G575N CPT-5170 150 0 % - medium no cells 100 % - DMSO % Viability 100 kDa 50 10 0.01 0.1 10 0.01 0.1 10 10 0.01 0.1 10 0.01 0.1 10 Conc.[µM 100 ] 0 -4 -3 -2 -1 0 1 2 75 GSPT1 logC logC [μM] [M] CPT-5170 CP
Slide 29: CPT-5170 and CPT-6281 induce apoptosis in Hep3B HCC cells
CPT-5170 and CPT-6281 induce apoptosis in Hep3B HCC cells CPT-5170 150 125 100% - DMSO 0% - No cells % Viability 100 75 50 25 0 -4 -3 -2 -1 0 1 2 LogC [µM] CPT-6281 150 125 100% - DMSO 0% - No cells % Viability 100 75 50 25 0 -4 -3 -2 -1 0 1 2 LogC [µM] Business Use Only | Do not use without written
Slide 30: Efficacy of GSPT1 degradation correlates with cytotoxicity in HCC cell lines
Efficacy of GSPT1 degradation correlates with cytotoxicity in HCC cell lines -AAC-215 CPT-6281 CPT-ABS-752 10 -4 SNU-886 SNU-182 SNU-423 SNU-886 SNU-423 HuH-1 SNU-182 U-398 10 -5 CTG (Abs IC50, M) HuH-1 10 -6 10 -7 HuH-7 SNU-398 Hep3B JHH-7 10 -8 10 20 30 40 50 60 70 80 90 0 0 10 50 60 70 80 90 0 10
Slide 31: Combinatorial treatment results in a strong synergistic effect
Combinatorial treatment results in a strong synergistic effect SNU-886, N=3 HuH-7, N=2 150 150 marketed drug marketed drug 100% - DMSO 0% - No cells 100% - DMSO 100 CPT-6281 0% - No cells 100 % Viability CPT-5170 % Viability increasing increasing concentrations of concentrations of CPT-5170 with a 2
Slide 32: CPT-5170 and CPT-6281 Exhibited Very Strong Efficacy and Induced Tumor Regression
CPT-5170 and CPT-6281 Exhibited Very Strong Efficacy and Induced Tumor Regression at Low Doses CPT-5170 CPT-5170 1750 350 1500 300 Vehicle Tumor volume (mm3) Tumor volume (mm3) 1250 250 100mg/kg 100mg/kg Mean +/- SEM Mean +/- SEM 1000 50mg/kg 200 50mg/kg 750 25mg/kg 150 25mg/kg 10mg/kg HEP3B cells 5
Slide 33: In vivo PoC: suppressed growth and induced regression of Hep3B xenografts
In vivo PoC: CPT-5170 and CPT-6281 suppressed growth and induced regression of Hep3B xenografts Vehicle CPT-6281 100 mg/kg Business Use Only | Do not use without written consent of Captor Therapeutics Inc. © 2022 33
Slide 34: Summary
Summary CPT-5170 and CPT-6281: • are very potent molecular glues with high potential as a novel therapy for HCC • induce degradation of GSPT1, SALL4 and of a novel undisclosed target • induce Integrated Stress Response and apoptosis in Hep3B cells • lead to robust tumor regression in an Hep3B xenogr
Slide 35: Plans
Plans 1. Evaluation of CPT-5170 and CPT-6281 efficacy in PDX models of HCC 2. Evaluation of combinatorial therapy in HCC animal models 3. Characterization of the the benefits of degrading the undisclosed target 4. Identification of additional cancers sensitive to CPT-5170 and CPT-6281 Business Use O
Slide 36: Captor Therapeutics S.A contact details
Captor Therapeutics S.A ul. Dunska 11 54-427 Wroclaw, Poland Captor Therapeutics GmbH Gewerbestrasse 24 4123 Allschwil, Switzerland IR Contact: Marta Święcicka m.swiecicka@captortherapeutics.com Media and IR Contact: captortherapeutics@pov.pl All images by Piotr Piatek
Slide 37: Projects are co-financed by the European Regional Development Fund
Projects are co-financed by the European Regional Development Fund: Discovery and development of a new clinical drug candidate for the eradication of cancer stem cell in the treatment of hepatocellular carcinoma, through degradation of oncofetal transcription factor (POIR.01.01.01-00-0740/19) Discov