Lu 177 zalsenertant tetraxetan (3BP-227) / Ipsen, 3B Pharma, AstraZeneca - LARVOL DELTA

Stereochemistry and Its Effects on Retention time of an NTSR1 Targeting Radiotherapeutic Agent (SNMMI 2026) - "The faster enzyme kinetics of the 2S-3S stereoisomer are consistent with previous literature. The in vitro and ex vivo SDS-PAGE showed bands consistent with the MW of CCs. The biodistribution results showed a favorable initial uptake in the tumor."

Colorectal Cancer • Renal Cell Carcinoma • Solid Tumor • CTSB • CTSS

Advances in research on radiopharmaceuticals targeting NTSR1. (PubMed, Eur J Med Chem) - "Currently, radioligands such as the small-molecule antagonist 3BP-227 and the peptide agonist [68Ga]DOTA-NT-20.3 have entered clinical trials...It emphasizes their applications in tumor imaging diagnosis and targeted radiotherapy. The article aims to provide a reference for drug development based on NTSR1 ligands."

Journal • Review • Oncology • NTS

Design and Evaluation of Dual-Targeted Radionuclide Therapeutics for NTS1 with Improved Tumor Retention through Endolysosomal Trapping. (PubMed, ACS Omega) - "However, all experimental constructs containing the irreversible inhibitor had higher tumor retention (17.8 ± 1.5-28 ± 7%) as a percentage of initial uptake compared to [ 177 Lu]-Lu-3BP-227 (13 ± 2%). In conclusion, this study provides valuable insights into the structure-activity relationships of these dual-targeted constructs for future development to improve tumor uptake and reduce the renal retention of NTS1-targeted radiotherapeutics."

Journal • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor • CTSB

Enhanced Retention of NTSR1-Targeted Radionuclide Therapeutics via Covalent Inhibitors in Pancreatic, Colorectal, and Prostate Cancer Models. (PubMed, Mol Pharm) - "Incorporating the covalent inhibitor in [177Lu]Lu-NA-ET1 resulted in an improved retention and radiation dose delivery profile compared to [177Lu]Lu-3BP-227. Examination of the therapeutic potential of [177Lu]Lu-NA-ET1 and further exploration of the chemical biology of this approach is underway."

Journal • Preclinical • Colorectal Cancer • Genito-urinary Cancer • Oncology • Pancreatic Cancer • Prostate Cancer • Solid Tumor • CTSS

Elucidation of the Impact of Linker Modifications on the Biological Efficacy of Antagonistic NTSR1-Targeted Radionuclide Therapeutics for Colorectal Cancer (SNMMI 2024) - "This research demonstrated the successful incorporation of endolysosomal trapping inhibitors into the structure of NTSR1-TRTs to afford five novel constructs that achieved enhanced tumor retention relative to 177Lu-3BP-227. Substitution of aminoalkoxy-containing linkers resulted in prominent increases in renal uptake and retention. Further investigation into the impact of linker modifications in NTSR1- and other receptor-targeted antagonistic TRTs can improve the biological efficacy of agents."

Clinical • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Development of 177Lu-FL-091 for the treatment of NTSR1-positive cancers (SNMMI 2024) - "In PC-3 xenograft model that was negative for AR or PSMA expression, single dose of 177Lu-FL-091 at 37 MBq induced >30% tumor shrinkage in all treated mice (Figure E). NTSR1 was found to be highly expressed across multiple types of cancers, especially in head and neck and colorectal cancer. FL-091 displayed enhanced binding affinity to NTST1 and antagonist activity compared to 3BP-227. In addition, 177Lu-FL-091 demonstrated improved in vivo biodistribution profile vs."

Colorectal Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Genito-urinary Cancer • Head and Neck Cancer • Hepatology • Oncology • Pancreatic Cancer • Prostate Cancer • Solid Tumor • FOLH1

Chelator boosted tumor-retention and pharmacokinetic properties: development of 64Cu labeled radiopharmaceuticals targeting neurotensin receptor. (PubMed, Eur J Nucl Med Mol Imaging) - "Through the side-by-side comparison, [64Cu]Cu-4b was identified as the lead agent for further evaluation based on its high and sustained tumor uptake and moderate liver uptake. It can not only be used to efficiently detect NTSR1 expression in lung cancer (for diagnosis, patient screening, and treatment monitoring), but also has the great potential to treat NTSR-positive lesions once chelating to the beta emitter 67Cu."

Journal • PK/PD data • Lung Cancer • Oncology • Solid Tumor • NRAS

Study to Evaluate the Safety and Activity (Including Distribution) of 177Lu-3BP-227 in Subjects With Solid Tumours Expressing Neurotensin Receptor Type 1. (clinicaltrials.gov) - P1 | N=14 | Terminated | Sponsor: Ipsen | Phase classification: P1/2 ➔ P1

Phase classification • Colorectal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Oncology • Osteosarcoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Sarcoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Examination of Charge Modifications of an Endolysosomal Trapping Inhibitor in an Antagonistic NTSR1-Targeted Construct for Colon Cancer. (PubMed, Bioconjug Chem) - "These four Lu-labeled, ET-enhanced, NTSR1-targeted agents (Lu-NA-ET1-4), along with the structurally analogous Lu-3BP-227, currently in clinical trials, underwent a battery of in vitro assays using HT-29 xenograft colon cancer cells to examine their NTSR1 binding, internalization and efflux, inhibition, and adduct formation properties...This study demonstrates that the ETs can be successfully incorporated into antagonistic NTSR1-targeted constructs without compromising their adduct formation capabilities. Based on these results, further exploration of the endolysosomal trapping approach is warranted in NTSR1- and other receptor-targeted antagonistic constructs."

Journal • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Positron Emission Tomography Imaging of Neurotensin Receptor-Positive Tumors with Ga-Labeled Antagonists: The Chelate Makes the Difference Again. (PubMed, J Med Chem) - "A small molecule NTS antagonist, named [Lu]Lu-IPN01087, is currently evaluated in phase I/II clinical trials for the targeted therapy of neurotensin receptor-positive cancers...Its rapid clearance from healthy tissues led to high tumor-to-organ ratios, resulting in highly contrasted PET images. These results were confirmed on subcutaneous xenografts of AsPC-1 tumor cells, a model of NTS-positive human pancreatic adenocarcinoma."

Journal • Gastrointestinal Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer

Study to Evaluate the Safety and Activity (Including Distribution) of 177Lu-3BP-227 in Subjects With Solid Tumours Expressing Neurotensin Receptor Type 1. (clinicaltrials.gov) - P1/2; N=14; Terminated; Sponsor: Ipsen; N=320 ➔ 14; Trial completion date: Aug 2022 ➔ Apr 2021; Recruiting ➔ Terminated; Due to agreement to transfer rights for IPN01087 to an external partner, not due to safety concerns

Clinical • Enrollment change • Trial completion date • Trial termination • Colorectal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Oncology • Osteosarcoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Sarcoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Fusion Pharmaceuticals Announces Closing of Acquisition of IPN-1087, a Small Molecule Targeting NTSR1, from Ipsen (PRNewswire) - "Fusion Pharmaceuticals...announced it has completed the acquisition of Ipsen's (Euronext: IPN; ADR; IPSEY) intellectual property and assets related to IPN-1087. IPN-1087 is a small molecule targeting neurotensin receptor 1 (NTSR1), a protein expressed on multiple solid tumor types. Fusion intends to use IPN-1087 to create an alpha-emitting radiopharmaceutical, FPI-2059, targeting solid tumors expressing NTSR1."

M&A • Oncology • Solid Tumor

Fusion Pharmaceuticals to Expand Pipeline with Acquisition of IPN-1087, a Small Molecule Targeting NTSR1, from Ipsen (Canada Newswire) - "Fusion Pharmaceuticals Inc...announced it has entered into an asset purchase agreement (APA) to acquire Ipsen's (Euronext: IPN; ADR; IPSEY) intellectual property and assets related to IPN-1087. IPN-1087 is a small molecule targeting neurotensin receptor 1 (NTSR1), a protein expressed on multiple solid tumor types. Fusion intends to use IPN-1087 to create an alpha-emitting radiopharmaceutical, FPI-2059, targeting solid tumors expressing NTSR1....Under the terms of the APA, Fusion will issue to Ipsen 400,000 shares of its common stock upon closing and an additional 200,000 shares upon the achievement of a patent-related milestone."

M&A • Oncology • Solid Tumor

Study to Evaluate the Safety and Activity (Including Distribution) of 177Lu-3BP-227 in Subjects With Solid Tumours Expressing Neurotensin Receptor Type 1. (clinicaltrials.gov) - P1/2; N=320; Recruiting; Sponsor: Ipsen; Trial completion date: Aug 2026 ➔ Aug 2022

Clinical • Pan tumor • Trial completion date • Colorectal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Oncology • Osteosarcoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Sarcoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Study to Evaluate the Safety and Activity (Including Distribution) of 177Lu-3BP-227 in Subjects With Solid Tumours Expressing Neurotensin Receptor Type 1. (clinicaltrials.gov) - P1/2; N=320; Recruiting; Sponsor: Ipsen; Trial completion date: Apr 2023 ➔ Aug 2026; Trial primary completion date: Apr 2021 ➔ Aug 2021

Clinical • Pan Tumor • Trial completion date • Trial primary completion date • Colorectal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Oncology • Osteosarcoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Sarcoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Study to Assess the Safety and Efficacy of Intravenous Injection of the Imaging Agent 111In-IPN01087 in Patients With Locally Advanced or Metastatic Pancreatic or Colorectal Cancer. (clinicaltrials.gov) - P1; N=70; Not yet recruiting; Sponsor: Ipsen

Clinical • New P1 trial • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Study to Evaluate the Safety and Activity (Including Distribution) of 177Lu-3BP-227 in Subjects With Solid Tumours Expressing Neurotensin Receptor Type 1. (clinicaltrials.gov) - P1/2; N=320; Recruiting; Sponsor: Ipsen; Trial completion date: Mar 2022 ➔ Apr 2023; Trial primary completion date: Apr 2020 ➔ Apr 2021

Clinical • Pan Tumor • Trial completion date • Trial primary completion date • Colorectal Cancer • Ewing Sarcoma • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Oncology • Osteosarcoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck