Captor Therapeutics Sa · GPW:CTX
Captor Therapeutics Sa — Investor Day (December 2023)
21 slides from Captor Therapeutics Sa's investor day presentation, Dec 1, 2023
Slide 1: Conducting research at the drug discovery stage using selected Captor projects
Conducting research at the drug discovery stage using selected Captor projects Piotr Kowalczyk – Principal Scientist Drug Discovery 1 December 2023 CONFIDENTIAL | 2023
Slide 2: Piotr Kowalczyk – education
Piotr Kowalczyk – education 1992 – 1997: Warsaw University, Biology Faculty, Genetic Department MSc with specialization in molecular biology 1997 – 2001: Medical Centre for Postgraduate Education, Warsaw Oncology Center in Warsaw, Gastroenterology Department CENTRUM ONKOLOGII – INSTYTUT IM. MARII SK
Slide 3: Piotr Kowalczyk – professional experience
Piotr Kowalczyk – professional experience 2019 - 2021 : OncoArendi Therapeutics (Molecure), R & D Department senior scientist / project leader - development of small molecule inhibitors of chitin binding proteins (YKL-40) for the cancer and autoimmune disorders treatment 2010 - 2018: Selvita (RYVU),
Slide 4: Targeting MCL-1 in cancer
Targeting MCL-1 in cancer MCL-1 as a molecular target MCL-1 role in cancer • several MCL-1 inhibitors have been developed during the past decade • is involved in the regulation of apoptosis versus cell survival, and in and some of them have entered clinical trials, but no drugs have the maintenance
Slide 5: MCL-1 as a target in numerous anticancer therapies
MCL-1 as a target in numerous anticancer therapies MCL-1 is a key mechanism of drug resistance in cancer cells Highly attractive target serving as a major survival signal in numerous cancers Haematological malignancies Multiple Myeloma (MM) Acute Myeloid Leukaemia (AML) Non-Hodgkin Lymphoma (NHL) Se
Slide 6: Principle of targeted protein degradation
Principle of targeted protein degradation 6 CONFIDENTIAL | 2023
Slide 7: Project specific screening cascade
Project specific screening cascade New compounds Cell biology Biophysics Viability assay Binary complex Resistant cell line: Sensitive cell line: SPR: Mcl1 FP: CRBN ARH-77 MV4-11 1% FBS; 24h 1% & 10% FBS; 24 h Ternary complex WB AlphaLisa MV4-11; 1% FBS; 6h Compound ranking & selection pIC50_sensiti
Slide 8: CPT-2036 in vitro potency
CPT-2036 in vitro potency Viability assay – CTG Degradation assay – WB (24 h treatment) (6 h treatment) AML cell line: MV4-11 CPT-2036 AML cell line: MV4-11 inhibitor of apoptosis MV-4-11 120 w/o inh. of apoptosis w/ inh. of apoptosis Normalised MCL-1 150 100 IC50 = 150 nM abundance [%] Viability (%
Slide 9: CRBN and proteasome dependency in OPM-2 cells
CRBN and proteasome dependency in OPM-2 cells CPT-2036 OPM-2 cells were pre-treated with the ligand or the inhibitor for 1 h and then treated with compounds in 1% FBS for 6 hours. CPT AAB-889 – MG-132 (proteasome inhibitor), CPT-AAB-952 – CRBN ligand (hydroxy-thalidomide) CPT-2036 induces MCL-1 degr
Slide 10: Cell line and PBMCs sensitivity to CPT-2036 & CPT-908
Cell line and PBMCs sensitivity to CPT-2036 & CPT-908 120 pIC50 Cell line CPT-2036 CPT-908 100 MV-4-11 6.5 ± 0.1 8.5 ± 0.2 Viability (%) 80 MV-4-11 Ven-resistant - 11.5 (N=1) 60 MV-4-11 Ven-resistant + - 12.0 (N=1) Venetoclax 40 WSU-DLCL-2 5.4 ± 0.2 7.6 ± 0.1 DMS 114 6.2 ± 0.3 7.8 ± 0.1 20 OPM-2 6.6
Slide 11: High potency of CPT-908 in AML ex vivo models
High potency of CPT-908 in AML ex vivo models pIC50 values of tested compounds in each of the CPT-908 is more potent than ABS-994 in most of the 30 AML ex vivo models tested models 10 10 CTG-3950 CTG-4044 CTG-3950 CTG-4044 9 9 TP53_mutated pIC50 (CPT-908) 8 8 pIC50 7 7 6 6 TP53_mutated 5 5 TP53_muta
Slide 12: Strong PD effect upon single injection of CPT-2036 in mice
Strong PD effect upon single injection of CPT-2036 in mice CPT-2036 (50mg/kg) Vehicle ABS-836 (50 mg/kg) 2h 2h 4h 6h 8h kDa 37 MCL-1 25 15 Cl Caspase 3 10 50 Total protein 37 Vehicle 12h 24h 48h kDa 37 MCL-1 25 15 Cl Caspase 3 10 50 37 Total protein CB-17 SCID females, MV4-11 xenografts (tumour volu
Slide 13: Strong PD effect upon single injection of CPT-908 in mice
Strong PD effect upon single injection of CPT-908 in mice CPT-908 (50mg/kg) MV-4-11 Vehicle ABU-098 (50 mg/kg) 125 Relative MCL-1 abundance [%] 2h 2h 4h 8h 12h 24h 48h kDa 50 100 37 MCL-1 150 PARP 75 100 75 Cl PARP 20 50 15 Cl Caspase 3 50 25 37 Total protein 0 Vehicle 2h 4h 8h 12h 24h 48h CB-17 SCI
Slide 14: Efficacy of CPT-2036 & CPT-908 in MV4-11 leukaemia model
Efficacy of CPT-2036 & CPT-908 in MV4-11 leukaemia model Tumour volume on 18th treatment day Δ inhibition 3500 - ANOVA - Vehicle Compound Dose [mg/kg] (day 18) [%] Tumour volume [mm3] (mean ± SEM) 3000 ✱✱✱✱ ✱✱✱✱ 2500 ✱✱✱✱ 75 107 ✱✱✱✱ 2000 CPT-2036 25 44 CPT-2036 1500 5 10 1000 500 CPT-908 75 80 0 ic
Slide 15: CPT-2036 in combination with chemotherapeutic agents
CPT-2036 in combination with chemotherapeutic agents CPT-2036 100 Bliss synergy score MV-4-11 75 Co-treatment with CPT-2036 and different chemotherapeutic agents 50 in MV4-11 and DMS 114 for 72 h. Viability assessed by CTG assay. DMS 114 25 i i Ki i i i i ne EK FR T3 L2 R FR BT TO i BC tid FL EG M F
Slide 16: ADME properties of CPT-2036 & CPT-908
ADME properties of CPT-2036 & CPT-908 CPT-2036 CPT-908 ASSAY Parameter mouse monkey human mouse monkey human Remaining 59.2 - 85.0 0.2 102.9 83.5 @120 min [%] Plasma stability T-half [min] > 120 - > 120 < 15 > 240 > 240 FU 0.06 0.02** < 0.01 NC* - N/A*** PPB Recovery [%] 36.0 65.4** 99.3 NC* - 100.7
Slide 17: CPT-2036 regresses tumors in combination with venetoclax
Highly potent CPT-2036 regresses tumors in mice at low dose when used in combination with venetoclax 2500 Vehicle, Q3D/IV Vehicle, QD/PO Tumor volume [mm3] 2000 Vehicle, Q3D/IV – QD/PO CPT-2036, 25 mpk 1500 1000 Venetoclax, 7.5 mpk 500 CPT-2036, 25 mpk 0 + Venetoclax, 7.5 mpk 0 5 10 15 20 Day of tre
Slide 18: Strong PD effect of both CPT-908 & CPT-2036 in NHP PBMCs
Strong PD effect of both CPT-908 & CPT-2036 in NHP PBMCs Internal control CPT-2036 0.1 mg/kg 1 mg/kg 10 mg/kg kDa -24 3 6 -24 3 6 -24 3 6 Treatment time [h] 50 37 MCL-1 50 CPT-2036 0.1 mg/kg 37 Total protein CPT-2036 1 mg/kg CPT-2036 10 mg/kg Internal control CPT-908 0.1 mg/kg CPT-908 CPT-908 1 mg/k
Slide 19: Troponin I levels in plasma of NHPs after treatment with MCL-1 degraders
Troponin I levels in plasma of NHPs after the treatment with MCL-1 degraders cTnI levels in plasma of treated NHPs (fold change relative to pre-dose conc.) 250 200 Concentration positive CPT-2036 CPT-2036 CPT-908 CPT-908 control Vehicle IV 3 mg/kg 10 mg/kg 3 mg/kg 10 mg/kg 150 100 50 0 12 24 12 24 1
Slide 20: MCL-1 degraders offer pharmacology distinct from inhibitors
MCL-1 degraders offer pharmacology distinct from inhibitors • MCL-1 degraders lead to a drop of MCL-1 levels, unlike inhibitors that accumulate MCL-1 • Reduction of MCL-1 by 50-70% results in apoptosis induction (monoallelic KO of MCL-1 is viable and without phenotype) • Optimized degraders, CPT-203
Slide 21: Captor Therapeutics S.A ul. Duńska 11 54-427 Wrocław, Poland
Captor Therapeutics S.A ul. Duńska 11 54-427 Wrocław, Poland Captor Therapeutics GmbH Hegenheimermattweg 167A 4123 Allschwil, Switzerland Contact: investor.relations@captortherapeutics.com 21 CONFIDENTIAL | 2023