Impact of Pre-Administration of Anti-IGF-1R Antibody FPI-1175 on the Dosimetry, Tumor Uptake, and Pharmacokinetics of the IGF-1R Targeted Theranostic Imaging Agent [111In]-FPI-1547 in Patients with Solid Tumors

SNMMI 2022 Publication # 2275 Impact of Pre-Administration of Anti-IGF-1R Antibody FPI-1175 on the Dosimetry, Tumor Uptake, and Pharmacokinetics of the IGF-1R Targeted Theranostic Imaging Agent [111In]-FPI-1547 in Patients with Solid Tumors Andrew Scott1, Fred Saad2, Daniel Juneau2, Michael Brown3, Ian Kirkwood4, Michelle Nottage4, John Rhoden5, Julia Kazakin5, Joanne Schindler5, Nick Baca6, Rick Sparks6, James O’Leary5, Eric Burak5 1Olivia Newton-John Cancer Wellness & Research Centre, Heidelberg, VIC, Australia, 2Centre Hospitalier de l’Université de Montréal, Université de Montréal, Montreal, QC, Canada, 3Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, SA, Australia, 4South Australia Medical Imaging, Royal Adelaide Hospital, Adelaide, SA, Australia, 5Fusion Pharmaceuticals, Hamilton, ON, Canada, 6CDE Dosimetry Services, Inc. Knoxville, TN, USA Pre-Administration of Cold Ab Increases Tumor Delivery of Radiopharmaceutical Therapies (RPT) (1) Saturate natural sinks and (2) Block sites of endogenous Ab binding Non-Tumor Tissue Tumor (3) Improve PK, e.g., increase circulating Hot Ab (4) Drive increase binding to tumor targets Pre-dosing with Cold Ab can Cold Ab = unconjugated/unlabeled Ab Hot Ab = radiolabeled conjugated Ab 2 Examples of RPT Dosing Regimens • 225Ac-J591: 225Ac-J591 composed of cold antibody at 20 mg; RP2D of 93.3 kBq/kg (Tagawa et al, JCO 2018) • 131I-tositumomab: Predose with tositumomab (450 mg) followed by 131I-tositumomab (35 mg) (Wahl, J Nucl Med 2005) • 177Lu-lilotomab satetraxetan: Predose with lilotomab (40 mg) followed by (177Lu)-lilotomab satetraxetan (Kolstad, Blood Adv 2020) SNMMI 2022 Publication # 2275 IGF1R: Overexpressed in many solid tumors 3 IGF-1R Implicated in: • Increased cellular proliferation • Metastatic potential • Cell survival • Chemotherapy and radiotherapy resistance Type I insulin-like growth factor receptor (IGF-1R) is a transmembrane protein which is overexpressed in solid tumors SNMMI 2022 Publication # 2275 "File:Protein IGF1R PDB 1igr.png" by Emw is licensed with CC BY-SA 3.0. [225Ac]-FPI-1434 Background 4 OO O H N O O O O N N N N O O OO O N H O 111In 4-Arm DOTA Chelator PEG3 Linker FPI-1175 Imaging [111In]-FPI-1547 4-Arm DOTA Chelator PEG3 Linker FPI-1175 Therapy “Hot Ab” OO O H N O O O O N N N N O O OO O N H O 225Ac [225Ac]-FPI-1434 SNMMI 2022 Publication # 2275 Theranostic Pair FPI-1175 Anti-IGF-1R Ab “Cold Ab” N H O FPX-01-01 is a Phase 1/2 study designed to determine the safety, tolerability, dosimetry and activity of [225Ac]-FPI-1434, a radioimmunoconjugate targeting IGF-1R (NCT03746431) Cold Antibody Sub-Study (CASS) within FPX-01-01, A Phase 1/2 Study of [225Ac]-FPI-1434 5  CASS: A cold Ab sub-study was conducted concurrently with Phase 1 dose escalation to determine the safety, tolerability, and effect of administration of varying doses of FPI-1175 on [111In]-FPI-1547 biodistribution, dosimetry and tumour uptake. • FPI-1175 was administered at 2 different mass doses: (1) 0.5 mg/kg and (2) 1.5 mg/kg • Each patient initially received [111In]-FPI-1547 without FPI-1175 and then [111In]-FPI-1547 preceded by FPI-1175 • After participating in CASS, patients who continued to meet study eligibility criteria could receive multiple administrations of [225Ac]-FPI-1434 without pre-dose administration of FPI-1175 • A Target to Background ratio (skeletal muscle) of 2:1 qualified patients to receive [225Ac]- FPI-1434 SNMMI 2022 Publication # 2275 FPX-01-01 CASS: Imaging Schedule 6 Week 4Week 3Week 2Week 1 SNMMI 2022 Publication # 2275 [111In]-FPI-1547 [111In]-FPI-1547FPI-1175 • Each patient served as their own control to evaluate extent of any changes in biodistribution and organ dosimetry 2-3 Days 24 hrs 2-3 Days 6-8 Days 24 hrs 0.5-2 hrs 2-3 Days 2-3 Days0.5-2 hrs 24 hrs [225Ac]-FPI-1434 FPX-01-01 CASS: Baseline Demographics, Cohort Assignment and Safety Patient # Tumor Type Age Sex Prior Therapy Prior RT [111In]-FPI- 1547 FPI-1175 Imaging Study Results 1 Prostate Ca, stage IV 62 M 4 Yes 185 MBq 0.5 mg/kg Sufficient tumor uptake, eligible to receive [225Ac]-FPI-1434 2 CRC, stage IV 36 F 3 No 185 MBq 0.5 mg/kg Sufficient tumor uptake, eligible to receive [225Ac]-FPI-1434 3 CRC, stage IV 52 M 4 No 185 MBq 1.5 mg/kg Low tumor uptake, not eligible to receive [225Ac]-FPI-1434 4 Prostate Ca, stage IV 70 M 5 Yes 185 MBq 1.5 mg/kg Low tumor uptake, not eligible to receive [225Ac]-FPI-1434 5 Melanoma, stage IV 57 F 2 No 185 MBq 1.5 mg/kg Sufficient tumor uptake, eligible to receive but progressed prior to treatment 7 Safety The known safety profile of FPI-1175 and [111In]-FPI-1547 did not change • No FPI-1175-related events were reported • One [111In]-FPI-1547-related event reported: Grade 1 constipation in one patient Imaging with pre-dose administration of FPI-1175 was well tolerated SNMMI 2022 Publication # 2275 FPX-01-01 CASS Patient #1 with Prostate Ca 111In-FPI-1547 SPECT Multiplanar Views ~48hrs 111In-FPI-1547 FUSED SPECT / CT Without FPI-1175 (Cold Ab) With 0.5 mg/kg FPI-1175 (Cold Ab) Increased lesion uptake lesion lesion lesion lesion 8 SNMMI 2022 Publication # 2275 111In-FPI-1547 FUSED SPECT / CT 111In-FPI-1547 SPECT 111In-FPI-1547 SPECT FPX-01-01 CASS: Patient #4 with Prostate Ca Multiplanar Views ~48hr Without FPI-1175 (Cold Ab) With 1.5 mg/kg FPI-1175 (Cold Ab) 111In-FPI-1547 FUSED SPECT / CT lesionlesion liver / spleen Spleen decrease Liver increase 9 SNMMI 2022 Publication # 2275 111In-FPI-1547 FUSED SPECT / CT 111In-FPI-1547 SPECT FPX-01-01 CASS: Change in Individual Lesion Uptake with Pre-administration of FPI-1175 (Cold Ab) 10 Change in lesion uptake was observed regardless of anatomic sites, which included: • bone (pelvis, sacrum, thoracic spine) • mediastinal mass • lung • liver • lymph nodes In general, a positive change was noted with pre-administration of 0.5 mg/kg versus 1.5 mg/kg FPI-1175 SNMMI 2022 Publication # 2275 Pt #1 Pt #1 Pt #1 Pt #2 Pt #2 Pt #2 Pt #3 Pt #3 Pt #4 Pt #4 Pt #4 Pt #5 Pt #5 Pt #5 0 5 10 15 20 25 Without Cold Antibody With Cold Antibody Lesion/Muscle Uptake Ratio 0.5 mg/mL FPI-1175 1.5 mg/mL FPI-1175 FPX-01-01 CASS Pharmacokinetics (PK) The cold antibody dosing regimen extends the [111In]-FPI-1547 half-life and increases AUC PK profile of [111In]-FPI-1547 is comparable at 0.5 mg/kg and 1.5 mg/kg FPI-1175 antibody ■ Doses ≥ 0.5 mg/kg saturate the antigen sink and linear PK is observed ■ PK at doses ≥ 0.5 mg/kg is similar to the reported PK of the parental mAb SNMMI 2022 Publication # 227511 [111In]-FPI-1547 PK Parameters (Mean ± SD) Cmax (ng-eq/mL) AUCinf (ng-eq*hr/mL) T1/2 (hr) No FPI-1175 555 ± 155 11600 ± 5300 37 ± 8.0 0.5 mg/kg FPI-1175 999 ± 273 133000 ± 82700 104 ± 43 1.5 mg/kg FPI-1175 662 ± 277 56000 ± 44600 61 ± 47 N=5 for no cold; N=2 for 0.5 mg/kg FPI-1175; N=3 for 1.5 mg/kg FPI-1175 0 50 100 150 200 1 10 100 1000 10000 [111In]-FPI-1547 Plasma Concentration-Time Profile Hours [111In]-FPI-1547 (ng-Eq/g) No FPI-1175 0.5 or 1.5 mg/kg FPI-1175† †PK profiles of [111In]-FPI-1547 are comparable at 0.5 mg/kg (N=2) and 1.5 mg/kg (N=3) dose levels of FPI-1175 FPX-01-01 CASS Conclusions This imaging sub-study was designed to determine the effect of cold Ab (FPI-1175) on dosimetry/PK/safety to assist in selection of an appropriate dose of FPI-1175 for evaluation in combination with the therapeutic, [225Ac]-FPI-1434 Favorable gain in tumor lesion uptake versus normal tissue was noted with addition of FPI-1175 relative to [111In]-FPI-1547 alone ■ Results at 0.5 mg/kg were sufficient to saturate normal tissue sink and generally more favorable versus 1.5 mg/kg FPI-1175 ■ Sites of improved tumor lesion uptake were independent of anatomic location (bone, lung, liver, lymph nodes) Administration of [111In]-FPI-1547 with and without FPI-1175 was safe without any drug-related Serious Adverse Events or Dose Limiting Toxicities Currently exploring pre-administration of FPI-1175 at 0.5 mg/kg with increasing dose levels of [225Ac]-FPI-1434 12 SNMMI 2022 Publication # 2275

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