TLX250-CDx is a radiolabeled form of the antibody girentuximab, which binds to the tumor-specific antigen CAIX on clear cell renal cell carcinoma. Accumulation of this antibody in tumor tissue can be visualized by positron emission tomography scans (PET). This could fundamentally change therapy planning for renal cancer patients and avoid potentially unnecessary surgery. The diagnostic agent may also prove suitable for monitoring response to treatment, detecting metastases and diagnosing other kinds of tumors.
Under the name REDECTANE®, the project was developed up to an initial Phase III trial (REDECT) at Heidelberg Pharma AG and licensed in 2017 to the Australian firm Telix Pharmaceuticals Limited, Melbourne, Australia, (Telix). The license agreement also covers the development of a therapeutic radioimmunoconjugate program. Telix developed a modernized production process for the manufacture of the antibody girentuximab.
TLX250-CDx (89Zr-DFO-girentuximab) is an antibody radioactively labeled with zirconium-89 and has been tested by Telix in the ZIRCON study for imaging diagnostics of renal cancer using PET since August 2019. The study was carried out as a global multicenter Phase III trial at 36 study sites in Europe, Turkey, Australia, Canada, and the USA. A total of 300 renal cell cancer patients were dosed with TLX250-CDx resulting in 284 evaluable patients. Each patient received a single dose of TLX250-CDx followed by imaging, and a histological tumor sample from surgical resection was provided. The study determined the sensitivity and specificity of TLX250-CDx PET imaging to detect clear cell renal cell cancer (ccRCC) in comparison with histology as standard of truth determined from surgical resection specimens.
Telix reported positive date of the ZIRCON study in November 2022. The study results delivered a sensitivity of 86% and specificity of 87%, thus exceeding the thresholds required to demonstrate the ability of TLX250-CDx to reliably detect the clear cell phenotype and provide a non-invasive method of diagnosing the presence and spread of ccRCC.
The study has also met the key secondary endpoint, achieving 85% sensitivity and 89% specificity in detecting ccRCC in tumors <4 cm (“T1a” classification), currently a significant clinical challenge in the diagnosis of ccRCC.
These highly positive results demonstrate that TLX250-CDx provides a way to non-invasively diagnose clear cell renal cancer – until now this could only be determined by invasive biopsy or surgery which presents a higher burden or danger for patients.
TLX250-CDx has received “Breakthrough Designation” for TLX250-CDx from the US Food and Drug Administration (FDA). Based on these positive results Telix intends to file a Biologics License Application (BLA) for regulatory approval with the FDA and global regulatory agencies as a positron emission tomography/computed tomography (PET/CT) imaging agent for use in the characterization of indeterminate renal masses previously identified on CT or MRI as ccRCC or non-ccRCC. Potential future utility may include active surveillance, surgical staging and treatment response assessment. Telix is actively engaged in clinical research at leading cancer centres to demonstrate the potential of these indications.
Furthermore, Telix is preparing to launch an Expanded Access Program (EAP) to enable eligible patients to access TLX250-CDx to address unmet need and requests for access under the healthcare professional responsibility prior to marketing authorization.
Under Telix’s guidance a number of investigator-led studies of TLX250-CDx have been initiated, supporting the goal of indication expansion. In mid-2021, a Phase I study (ZiP-UP) of TLX250-CDx was launched to evaluate the feasibility of using it in detecting urothelial carcinoma or bladder cancer. ZiP-UP is the first in a series of studies that will harness TLX250-CDx to evaluate CAIX expression in cancers other than renal cancer. In October, Telix announced that a first patient had been dosed in a Phase II study of TLX250-CDx in patients with triple-negative breast cancer (OPALESCENCE); further collaborative studies are in the pipeline for ovarian, colorectal, head and neck, lung and pancreatic cancers.
Telix is also planning the further development of a therapeutic radioimmunoconjugate (177Lu-DOTA-girentuximab, TLX250) program based on the lutetium-177-labeled girentuximab antibody.
The IND application to conduct a Phase II (STARLITE 2) study was accepted by the FDA in September 2021. TLX250 is to be tested in the STARLITE 2 study as therapy for an estimated 29 patients with advanced clear cell renal cell carcinoma (ccRCC). The study will evaluate TLX250 in combination with the immunotherapy Opdivo® (nivolumab). The efficacy of combining immunotherapy with TLX250, as assessed by the number of tumors responding to the Telix therapy versus the current standard of care, will be tested. The first patient has been dosed in May 2022.
upamostat is an oral uPA/serine protease inhibitor, which has been developed by Heidelberg Pharma until Phase II. It is designed to block the activity of tumor-relevant serine proteases such as uPA, plasmin and thrombin to prevent tumor growth and metastasis.
In 2014, the development and commercialization rights for upamostat were outlicensed to Link Health Co., Guangzhou, China (Link Health) for China, Hong Kong, Taiwan and Macao, and RedHill Biopharma Ltd., Tel Aviv, Israel (RedHill) for the rest of the world.
RedHill is developing upamostat (RHB-107) in combination with RedHill’s other development candidate opaganib for the treatment of advanced cholangiocarcinoma, subject to approval from the FDA. Based on preclinical results showing strong anti-tumor activity of the combination of RHB-107 with opaganib, RedHill plans to enroll a third cohort in its ongoing Phase IIa study in cholangiocarcinoma to evaluate this combination therapy. In addition, RedHill announced a U.S. patent grant in 2020 for the combination of RHB-107 and opaganib for the oral treatment of solid tumors.
Furthermore RHB-107 is also tested for treating COVID-19. RHB-107 has demonstrated both antiviral and potential tissue-protective effects, with RHB-107 strongly inhibiting SARS-CoV-2 replication in a preclinical human bronchial tissue study. The candidate targets human serine proteases that are involved the virus’s entry into target cells. Because RHB-107 targets human cell factors and not the virus itself, RHB-107 is expected to be effective against emerging virus variants. RedHill started a Phase II/III trial with non-hospitalized patients in the USA in early 2021, dosing the first patient in February 2021. RedHill announced receipt in May 2021 of a Notice of Allowance from the US Patent and Trademark Office (USPTO) covering RHB-107 as a method for the treatment of COVID-19. Recruitment for Part A of the study has been completed and initial positive data from it were announced in March 2022.