Combination of IGF-1R Targeted Alpha Therapy with Olaparib Results in Synergistic Efficacy Against Colorectal and Lung Cancer Xenografts

Combination of IGF-1R targeted alpha therapy with olaparib results in synergistic efficacy against colorectal and lung cancer xenografts. M Hu, J Forbes, R Simms, Y Storozhuk, J Valliant, E Burak Fusion Pharmaceuticals, Hamilton, Ontario, Canada Copyright © 2021 Fusion Pharma Inc. All Rights Reserved IGF-1R: Ideal alpha therapeutic delivery mechanism ■ Overexpressed on the surface of cancer cells ■ Low expression on surface of normal tissue ■ Rapidly internalizing receptor to concentrate alpha- particles inside tumor cells Copyright © 2020 Fusion Pharmaceuticals Inc. All Rights Reserved2 FPI-1434: IGF-1R Targeted Alpha Therapeutic [225Ac]-FPI-1434 (Therapeutic) Attractive Therapeutic Potential: IGF-1R is expressed on nearly all tumor types Breast Colorectal Prostate Sarcomas NSCLC Pancreatic / NETs Adrenocortical carcinoma HCC H&N Single Dose Therapeutic Efficacy in a Colorectal Cancer (Colo-205) and NSCLC Tumor (A549) Xenograft Models Copyright © 2020 Fusion Pharmaceuticals Inc. All Rights Reserved3 P<0.005 vs Veh. @ 52 days Colo-205 0 50 100 150 200 0 500 1000 1500 Days after Treatment Initiation Tumor Volume (mm3) Vehicle Control [225Ac]-FPI-1434 (1.85 kBq)[225Ac]-FPI-1434 (7.4 kBq)[225Ac]-FPI-1434 (14.8 kBq) 0 10 20 30 0 2 4 6 8 10 Days after Treatment Initiation Relative Tumor Volume A549 (External Beam Radiation Resistant) 0 10 20 30 0 2 4 6 8 10 Days after Treatment Initiation Relative Tumor Volume Vehicle Control Antibody Control (8.2 g) [225Ac]-FPI-1434 (0.74 kBq) [225Ac]-FPI-1434 (1.85 kBq) [225Ac]-FPI-1434 (3.7 kBq) [225Ac]-FPI-1434 (7.4 kBq) [225Ac]-FPI-1434 (14.8 kBq) P<0.002 FPI-1434 Mechanism of Action: DSB Formation and Apoptosis Increase in DSBs and apoptosis was demonstrated in a dose- & time-dependent manner Involvement of cell death mechanisms other than apoptosis cannot be ruled out Copyright © 2020 Fusion Pharmaceuticals Inc. All Rights Reserved4 Time course at 14.8 kBq- IHC Time course at 14.8 kBq- WB Apoptosis FPI-1434 ATM P53 ATR P P P P Investigating Therapeutic Combinations Between FPI-1434 and the Double Stranded DNA Repair Inhibitor Olaparib (PARPi) Copyright © 2020 Fusion Pharmaceuticals Inc. All Rights Reserved5 Alpha-particles cause the breakage of tumor DNA that starts the process of tumor kill DDRi that inhibit the repair of DNA damage may synergize with FPI-1434 to amplify tumor kill (eg. olaparib) Combination of No-Effect Single Agent Doses of FPI-1434 and Olaparib Resulted in Enhanced Efficacy (Colo-205 Model) Copyright © 2020 Fusion Pharmaceuticals Inc. All Rights Reserved6 0.74 kBq FPI-1434 + 25 mg/kg Olaparib Days after treatment initiation Relative tumour volume (RTV) 0 10 20 30 40 50 0 2 4 6 8 10 Vehicle Olaparib (25 mg/kg) FPI-1434 (0.74 kBq) 0.74 kBq + 25 mg/kg 0 4 8 12 16 20 24 28Day FPI-1434 0.74, 1.85 or 3.7 kBq Olaparib 0, 25 or 50 mg/kg Final Olaparib Dose (Day 30) FPI-1434 + Olaparib; Combination Therapy at Multiple Dose Levels (Colo-205 Model) Copyright © 2020 Fusion Pharmaceuticals Inc. All Rights Reserved7 0.74 kBq FPI-1434 + Olaparib Days after treatment initiation Relative tumour volume (RTV) 0 10 20 30 40 50 0 2 4 6 8 10 Vehicle Olaparib (25 mg/kg) Olaparib (50 mg/kg) FPI-1434 (0.74 kBq) 0.74 kBq + 25 mg/kg 0.74 kBq + 50 mg/kg 1.85 kBq FPI-1434 + Olaparib Days after treatment initiation Relative tumour volume (RTV) 0 10 20 30 40 50 0 2 4 6 8 Vehicle Olaparib (25 mg/kg) Olaparib (50 mg/kg) FPI-1434 (1.85 kBq) 1.85 kBq + 25 mg/kg 1.85 kBq + 50 mg/kg 3.7 kBq FPI-1434 + Olaparib Days after treatment initiation Relative tumour volume (RTV) 0 10 20 30 40 50 0 2 4 6 8 Vehicle Olaparib (25 mg/kg) Olaparib (50 mg/kg) FPI-1434 (3.7 kBq) 3.7 kBq + 25 mg/kg 3.7 kBq + 50 mg/kg Strongest Combination Effect at the Lowest Single Agent Doses FPI-1434 Dose Level Copyright © 2020 Fusion Pharmaceuticals Inc. All Rights Reserved8 Combination of No-Effect Single Agent Doses of FPI-1434 and Olaparib Resulted in Enhanced Efficacy (A549 Model) 1.85 kBq FPI-1434 + 25 mg/kg Olaparib Days after treatment initiation Relative tumour volume (RTV) 0 10 20 30 0 2 4 6 Vehicle Olaparib (25 mg/kg) FPI-1434 (1.85 kBq) 1.85 kBq + 25 mg/kg 0 4 8 12 16 20 24 28Day FPI-1434 0.74, 1.85, 3.7 or 7.4 kBq Olaparib 0, 25 or 50 mg/kg Copyright © 2020 Fusion Pharmaceuticals Inc. All Rights Reserved9 FPI-1434 + Olaparib; Combination Therapy at Multiple Dose Levels (A549 Model) Strongest Combination Effect at Low Single Agent Doses 0.74 kBq FPI-1434 + Olaparib Days after treatment initiation Relative tumour volume (RTV) 0 10 20 30 0 2 4 6 Vehicle Olaparib (25 mg/kg) Olaparib (50 mg/kg) FPI-1434 (0.74 kBq) 0.74 kBq + 25 mg/kg 0.74 kBq + 50 mg/kg 1.85 kBq FPI-1434 + Olaparib Days after treatment initiation Relative tumour volume (RTV) 0 10 20 30 0 2 4 6 Vehicle Olaparib (25 mg/kg) Olaparib (50 mg/kg) FPI-1434 (1.85 kBq) 1.85 kBq + 25 mg/kg 1.85 kBq + 50 mg/kg 3.7 kBq FPI-1434 + Olaparib Days after treatment initiation Relative tumour volume (RTV) 0 10 20 30 0 2 4 6 Vehicle Olaparib (25 mg/kg) Olaparib (50 mg/kg) FPI-1434 (3.7 kBq) 3.7 kBq + 25 mg/kg 3.7 kBq + 50 mg/kg 7.4 kBq FPI-1434 + Olaparib Days after treatment initiation Relative tumour volume (RTV) 0 10 20 30 0 2 4 6 Vehicle Olaparib (25 mg/kg) Olaparib (50 mg/kg) FPI-1434 (7.4 kBq) 7.4 kBq + 25 mg/kg 7.4 kBq + 50 mg/kg FPI-1434 Dose Level Olaparib combination gave additional benefit to FPI-1434 therapy alone Combination of no-effect single agent doses resulted in enhanced efficacy in the Colo-205 model ■ 0.74 kBq FPI-1434 + 25 mg/kg Olaparib ■ Strongest combination effect appeared to occur at the lowest single agent doses ■ FPI-1434 effect dominates as the dose level escalates Combination of no-effect single agent doses resulted in enhanced efficacy in the radioresistant A549 model ■ 1.85 kBq FPI-1434 + 25 mg/kg Olaparib ■ Strongest combination effect appeared to occur at the low single agent doses ■ FPI-1434 effect dominates as the dose level escalates Copyright © 2020 Fusion Pharmaceuticals Inc. All Rights Reserved10 Summary of Studies with FPI-1434 + Olaparib Combinations

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